BCRP funds support research projects and training of both beginning and experienced scientists in breast cancer-related research
All Californians are touched by breast cancer, which has for decades taken a tragic toll among the people of this state. The cost of this disease is measured in human suffering, in lives lost, in wasted potential, and in medical care dollars. In 1997 alone, it is estimated that 180,200 women in the US (18,865 in California alone) were diagnosed with breast cancer and 43,900 (4,605 in California) succumbed to the disease. Over half of these women were in the prime of their lives (less than age 65), depriving children of their parents, the private and public sectors of experienced employees at their height of productivity, and decades of life for those who are lost. Recent data suggest that deaths from breast cancer may finally be decreasing, but the decrease has been small and does not reflect the following facts. First, a similar decrease in death rates was seen in the late 1970s, but was not sustained. Second, the current decrease could be due to an increase in the proportion of in situ and early stage cancers being diagnosed. Finally, death rates for African American women have actually increased over this same period.
In 1993, the California legislature recognized the need to respond to the continuing crisis of breast cancer. At that time, the state had no comprehensive public health plan to address breast cancer. With the passage of AB2055 and AB478, an ongoing source of funds from tobacco taxes was secured to support three arms of a state effort to decrease the human and economic cost of breast cancer in California. Forty-five percent of the funds was allocated to the Breast Cancer Research Program (BCRP), 50% to the Breast Cancer Early Detection Program and 5% to the California Cancer Registry. The California Breast Cancer Research Program was established at the University of California to spearhead research efforts on the causes, prevention, detection and cure of breast cancer. The Breast Cancer Research Council, which is an advisory committee to the University, determines the goals and priorities of the research program, establishes program policies, oversees peer review of submitted applications and makes funding recommendations. Review committees composed of expert scientists and breast cancer advocates from outside California are brought together each year to evaluate the scientific merit of applications.
The BCRP funds support research projects and training of both beginning and experienced scientists in breast cancer research. The funds that the Program directs to research on the causes, prevention, detection and cure of breast cancer are not just monies spent, but are investments in the future of Californians. By encouraging and identifying innovative research on breast cancer, and attracting and training some of the most talented and gifted scientists into this area of research, California is making an investment that can pay vital dividends for all Californians in years to come. The specific areas of research supported, as determined by the Breast Cancer Research Council with input from stakeholders across the state, include basic and clinical science, social and behavioral science, technology development, and public health research. New program areas in translational and collaborative research, as well as community partnerships, have been developed. State funding provides critical leverage in developing new scientific infrastructure and networks crucial for a comprehensive approach to the problem of breast cancer. The BCRP's challenge is to allocate funds rapidly and flexibly to assure that new and promising ideas are brought quickly to bear on the understanding and prevention, detection and cure of breast cancer.
1997 marked a year of important achievements for the BCRP. A portfolio of exciting new projects was funded, and the Program moved to fund new areas of research, disseminate research results, and translate research findings into practical application. In 1996-1997, the BCRP budget was $14.7 million. These funds support 66 multi-year projects to investigate the pathogenesis, etiology, prevention, early detection and treatment of breast cancer. The projects include large-scale research efforts, pilot studies of exciting and important new areas, collaborations among scientists from different fields and between scientists and community groups, and training projects for researchers early in their careers or new to breast cancer research. These studies are being carried out at universities (public and private), community agencies, medical centers, independent research institutes, federal laboratories, and biotechnology companies. The first projects funded by the Program in 1995 and 1996 are well underway, with progress reported here.
State funding provides critical leverage in developing new scientific infrastructure and networks
crucial for a comprehensive approach
to the problem of breast cancer.
As requested by the legislature, this Annual Report includes the following elements:
1. The number and dollar amounts of research grants, including the amount allocated to indirect costs.
2. The subject of research grants.
3. The relationship between federal and state funding for breast cancer research.
4. The relationship between each project and the overall strategy of the research program.
5. A summary of research findings including discussion of promising new areas.
6. The institutions and campuses receiving grant awards.
The report describes BCRP's recent activities, goals, progress, and plans for the challenges that lie ahead on the road to decreasing the human and economic cost of breast cancer for the people of California.
Status of Breast Cancer in California
While mammo-graphy has undoubtedly contributed to the decrease in mortality, no woman diagnosed with breast cancer today, no matter how small the tumor or how early it is detected, can be told that her cancer is cured.
Breast cancer is the most common cancer among women of any race or ethnic group in California, and is second only to lung cancer in cancer related deaths. In 1997 alone, it is estimated that 18,865 women in California were diagnosed with breast cancer and 4,605 died of the disease.The incidence of breast cancer in the state climbed steadily until 1987 during the time data were being collected (since 1973 for the San Francisco Bay and Los Angeles areas). Since 1987, rates have decreased slightly and now appear to have leveled off. Age-adjusted rates dropped from 111.8 per 100,000 in 1988 to 106 per 100,000 in 1993. These rates, however, varied markedly by race/ethnicity in the same time period, with non-Hispanic white women having the highest rate, followed by African American women, Hispanic women, and Asian American women, respectively. Among women younger than 50, however, African American women have a higher rate than white women.
Rates of death due to breast cancer have remained relatively constant in the United States during the last three decades, but have decreased approximately 14% in California since 1985 (about 2% per year). Unfortunately, this decrease has only been consistent and statistically significant for non-Hispanic white women. In addition, although African American women have a lower incidence of breast cancer than white women, the death rate is higher for African American women.
Mammography usage has increased markedly in the past decade, probably accounting in part for both the increased incidence of breast cancer and the decreased mortality. In 1987, only 46.7% of California women aged 40 and over reported ever having had a mammogram. By 1994, this figure had increased to 82.8%. Asian and Hispanic women, less educated women and those reporting a lower income, however, are less likely to have been screened and are therefore at greater risk for being diagnosed with breast cancer at a later stage. While mammography has undoubtedly contributed to the decrease in mortality, no woman diagnosed with breast cancer today, no matter how small the tumor or how early it is detected, can be told that her cancer is cured.
These data are most remarkable for the lack of significant change over time, despite advances in knowledge and in detection and treatment of breast cancer. It is hoped that the significant investment that California is now making will improve this reality in years to come.
BCRP
Activities
Strategic Objectives in Research Funding
The mission of BCRP is defined by its authorizing legislation as follows:
To support research efforts into the cause, cure, treatment, earlier detection, and prevention of breast cancer (from The Breast Cancer Act of 1993)
In keeping with the statutes, the Program is advised and overseen by an advisory council (the Breast Cancer Research Council). The Council is charged with developing the strategic objectives and priorities of the Program, and making final recommendations on which research grants should be funded.
Each spring, the Council meets to determine strategic objectives and funding priorities for the next year. The overall strategic objectives, as specified in the statutes, are:
- To fund research in fields that include, but are not limited to, biomedical science and engineering, the social, economic and behavioral sciences, epidemiology, technology development and translation, and public health.
- To fund innovative and creative research, with a special emphasis on research that complements, rather than duplicates, the research funded by the federal government.
- To consider a broad range of cross-disciplinary breast cancer research including, but not limited to, translational and technological research, including research regarding the development and translation of technologies of earlier detection; research regarding the cultural, economic, and legal barriers to accessing the health care system; research examining the link between breast cancer and environmental factors, including both natural and industrial chemicals, estrogen imitators, and electromagnetic fields.
Research Priority Issues
The Council, after careful deliberation, decided that the most effective use of the $14 million available in funding Cycle III was to concentrate research funding on a small number of key issues, focusing, to the extent possible, on areas that are not as well-funded by the federal government and other agencies. The priorities established by the Council were based on: 1) the importance of each area to the fight against breast cancer; 2) the Council's sense of the potential impact of funded research on the human and economic costs of breast cancer in the state of California; and 3) the funding patterns of the federal government and other agencies. In addition, the Program introduced new initiatives to: (1) challenge the research community to propose more innovative approaches to the problem of breast cancer, specifically including fostering collaborations between experienced researchers and community groups; and (2) provide strong support for collaborative "translational" research, i.e., work whose results can be moved rapidly into practical application, whether through grass-roots organizations or mainstream health care providers.
- The following six priorities were adopted:
- Enhance understanding of the etiology (causes) of breast cancer
- Enhance understanding of the pathogenesis (development) of breast cancer
- Develop new approaches to prevent breast cancer
- Develop more effective techniques for the earlier detection of breast cancer
- Increase access to services for the early detection of breast cancer
- Develop and test innovative models of care
- Explore innovative treatment modalities
Award Types
- Research Training: Maintenance of Needed Human Resources
The relentless rate of deaths due to breast cancer over the last several decades has prompted BCRP to provide for the training of new investigators -- the human resources needed to ensure progress in the fight against breast cancer. Through two award types, BCRP endeavors to attract new investigators to breast cancer research. Postdoctoral Fellowship Awards allow researchers early in their careers to receive research training in breast cancer issues. Sabbatical Awards provide support for experienced researchers to move into breast cancer research from another field. Together, these awards bring new minds into the fight against breast cancer, and ensure the human resources required to eradicate the disease.
Targeted Research Efforts
The Council identified two specific topics that they felt were (1) especially important to making progress in breast cancer research; and (2) not well supported by other research funding agencies. They set aside $1.5 million for each of the topics:
- Basic Breast Biology Relevant to Development of Breast Cancer This Request for Applications encouraged studies aimed at achieving a greater knowledge of the normal breast, through all stages of development and change, in order to better understand anomalous changes that may lead to cancer.
- Breast Cancer Prevention, Risk Identification and Risk Reduction This Request for Applications encouraged research that will enable more effective and appropriate prevention interventions by increasing our knowledge of modifiable breast cancer risk factors.
Innovation in Research
By identifying the specific priorities listed above, the Council has encouraged researchers to develop and explore innovative and risky concepts in areas that are most important in the fight against breast cancer. Innovative Developmental and Exploratory Awards (IDEAs) allow researchers to explore new concepts in breast cancer etiology, pathogenesis, prevention, and earlier detection that could lead to breakthroughs in these fields. Innovative Treatment and Models of Care Awards (ITaMoCAs) encourage development and testing of new treatment modalities or methods of delivering breast cancer care. Through these combined efforts of exploring new concepts and building on existing knowledge, the resulting improvements in prevention, detection and cure of breast cancer will advance the day when we can say with confidence that breast cancer is no longer a threat to the people of California.
New Initiatives in Collaboration
Two new award types were developed to stimulate and support collaborative research one for collaborations between experienced research scientists and community members/agencies (the Community-Initiated Research Collaboration (CIRC) Award), and one for collaborations between research scientists in different fields and institutions (the Translational Research Collaboration (TRC) Award). Both types of awards were designed to offer a one-year Pilot Award to foster the development of teams and their projects, with larger awards for full projects to be offered in 1998.
Special Considerations
Innovativeness- In keeping with the intent of the enabling legislation, the Council focuses on funding especially innovative and creative research. Every grant application is scored by reviewers on this aspect, which the Council weighs, in making its final funding recommendations.
Multidisciplinary Research
The Council encourages researchers to apply ideas from various fields to their research by collaborating across disciplines. This aspect of applications is also rated by reviewers and taken into consideration in making funding decisions.Translational Potential
A goal of the BCRP is to encourage the translation of scientific findings into practical applications that will make a difference to those at risk for, or diagnosed with, breast cancer. The potential of research findings to be translated into practical applications is rated by reviewers and taken into consideration in funding decisions.Focus on the Underserved
Another issue identified by the Council as critically important is the disparity in the incidence and mortality of breast cancer between different groups of Californians. Research which has the potential to reduce these disparities was specifically requested in the Call for Applications, identified by reviewers and considered by the Council in making funding recommendations.
Strategic Objectives in Research Support
The legislation that established BCRP lays forth additional objectives for the Program:
- "Provide for systematic dissemination of research results to the public and the health care communityin order that these findings may be applied to the planning, implementation, and evaluation of breast cancer-related programs."
- "Develop policies and procedures to facilitate the translation of research results into commercial, alternate technological, and other applications"
- "Development of appropriate linkages to nonacademic entities, including voluntary organizations, health care delivery systems, industry, government agencies, research entrepreneurs, and public officials."
Dissemination of Research Results
The BCRP is committed to disseminating the results of research that it funds, both to the scientific and medical communities (to facilitate the advancement of the understanding of breast cancer and its treatment among all involved) and to the public (as stakeholders in the Program). To this end, funded research is widely publicized in a variety of ways:
- Descriptions of new awards are published in the Compendium of Awards
- The progress of each project is summarized yearly and posted on
our web site- Final results of projects are described on the web site and in the
annual report- Publications are widely distributed and posted on the web site
Researchers also publish final results and present them at scientific conferences; these publications and presentations are tracked by BCRP. The 1997 California Breast Cancer Research Symposium served to disseminate results in a more interactive and visible fashion. A Council Committee, formed in 1997, is examining other means to achieve this aim.
1997 California Breast Cancer Research Symposium
- On September 16, 1997, BCRP hosted a symposium in Sacramento, that brought together individuals with a wide variety of backgrounds, but a common interest in determining the cause of, and cure for, breast cancer. This symposium was distinct from most other scientific symposiums in that it had a strong attendance by breast cancer advocates and the community at large.
The content and the composition of the symposium reflected the goals of BCRP. Over half of the more than 700 attendees characterized themselves as lay people. The symposium was designed for maximal exposure to all sides of the breast cancer fight. The activities available to the participants included: listening to the motivational keynote speakers; viewing artwork by and about people with breast cancer; visiting exhibits by non-profit breast cancer organizations; attending informational seminars about how to be funded to do breast cancer research; and attending talks and posters given by investigators who were funded by BCRP.
The keynote speakers exemplified the spirit of BCRP. They came from the worlds of science, breast cancer advocacy and governmental affairs. Former congresswoman and activist, Bella Abzug; renowned cell biologist and Director of Ernest O. Lawrence Berkeley National Laboratory's Life Sciences division, Mina J. Bissell, Ph.D.; former California state assemblywoman and sponsor of BCRP, Barbara Friedman; and breast cancer advocate and first Breast Cancer Research Council chair, Susan Claymon all gave their uniquely insightful views of the breast cancer movement landscape and the role of BCRP in it. In spite of their different perspectives on the fight against breast cancer, and perhaps because of it, there was a consensus of opinion that we will only succeed if people from all backgrounds combine their efforts.
The symposium provided an excellent showcase for the research funded by BCRP in the first three years of the program's existence. The research was presented in the form of posters and oral presentations. The more than 80 scientific presentations reflected the scope of high quality research funded by BCRP.
The information available at the BCRP symposium went beyond the BCRP sponsored research and emerging results. Forty non-profit organizations exhibited at the symposium. Their exhibits explained the current practical knowledge of what we can do to address breast cancer for ourselves, and as society as a whole. They passed on the current thinking about breast care and identified areas where political actions are needed.
Art exhibits brought forward the urgent need to conquer breast cancer.
In a world where symposiums can be emotionally reserved, this one touched the heart as well as the mind. The artwork was moving and kept the faces of people battling breast cancer foremost in the minds of the symposium participants.
Translation of Research Results into Practical Applications
A goal of the BCRP is to encourage the translation of research findings into practical applications that will make a difference to those at risk for, or diagnosed with, breast cancer. Facilitating this process is one of the charges of the Council. One strategy to achieve this goal has been outreach to California biotechnology researchers to encourage applications from those most involved in translational efforts.
In 1996, the Council and BCRP staff together developed a new award type (the Translational Research Collaboration Award, or TRC Award) to specifically solicit research proposals for translational research that arises from partnerships of research scientists from different fields and/or institutions (especially encouraging collaborations between academic and industry-based biotechnology researchers). This award type, offered for the first time in 1997, is helping to spread BCRP's principle of translation and collaboration throughout the research community in the state and is resulting in teams across the state who are poised to take research results and use them to develop products, treatments, and services. A Council Committee, formed in 1997, is examining other means to achieve this aim.
Collaboration with Communities
Close collaboration with organizations and individuals involved in breast cancer issues is a guiding principle
of the BCRP.
Close collaboration with organizations and individuals involved in breast cancer issues is a guiding principle of the BCRP. The 16-member Council includes five breast cancer advocates. These members are well respected for their years of exemplary service in the fight against breast cancer, and bring community perspectives to the Council's decisions. Each Review Committee that evaluates grant proposals includes two advocates who serve as voting members, and a third who serves as a non-voting observer from California and provides feedback on the process. This representation and participation at all levels of decision-making ensures that community and survivor viewpoints are considered in every Program activity.Information is disseminated to communities through distribution of the BCRP Bulletin, the Annual Report, the Compendium of Awards and conferences (which are open to all interested). An internet web site (http://www.ucop.edu/srphome/bcrp/) provides access to all BCRP documents including publications, Council meeting minutes and progress reports of funded projects.
In addition, the BCRP Director interacts with, and serves on various committees for other agencies and organizations, including the Department of Health Services Breast Cancer Early Detection Advisory Committee, the Breast Cancer Treatment Fund Advisory Committee, the American Cancer Society, the Lesbian Health Fund, The Breast Cancer Fund, and Breast Cancer Action.
These efforts establish effective dialogue with groups and individuals involved in breast cancer issues. They assure wide dissemination of research results, funding priorities that are important to those most affected by breast cancer, and funded projects that respond to these priorities.
As a result of feedback from the 1996 Public Advisory Meeting, the Council and staff together developed a new award type (the Community-Initiated Research Collaboration Award, or CIRC Award) to specifically solicit research proposals that arise from communities and are developed and carried out by partnerships of community members and experienced research scientists. This award type, offered for the first time in 1997, is helping to spread BCRP's principle of community involvement and collaboration throughout the research community in the state and is resulting in investigations in areas of research identified by, and important to, communities across the state.
In 1997, a number of research projects funded in 1995 and 1996 were completed. The results of these projects are summarized in this section. Other projects funded in 1995 and 1996 are still underway. Annual progress reports are submitted to the Program emerging findings are also reviewed in this section. Finally, a new portfolio of grants was awarded in these same areas in 1997. These new projects are also summarized in this section.
Abstracts of new projects, and Annual and Final Progress Reports of ongoing funded projects can be found on BCRP's internet web site.
Etiology: Finding the Causes
Identifying and understanding the factors that lead to breast cancer in individual women and in the population as a whole is crucial. Through this work, we can learn how to prevent breast cancer, for example, by discovering causative factors that can then be eliminated or reduced, or by identifying conditions that predispose a person to breast cancer and for which there may be compensating treatments.
Research Conclusions
A one-year study looking at genetic factors that might influence breast cancer risk was Vitamin D & Genetics of Vitamin D Receptor in Breast Cancer conducted by Dr. Sue A. Ingles, at the University of Southern California. Dr. Ingles questioned whether genetic variations in the Vitamin D receptor (VDR) are related to breast cancer incidence. (It has been speculated that variations in the VDR gene might affect breast cancer in a manner similar to the way it is known to affect bone mineral density.) Preliminary results indicate that women with a high-risk VDR genotype may be at a 3-10 fold increased risk of breast cancer compared to women with a low-risk genotype. It is suspected that the risk is affected directly or indirectly by the gene's influence on Vitamin D status, and further work on this issue is ongoing in another BCRP grant in the third cycle.
A second study, Genetic Susceptibility to Breast Cancer, conducted by Dr. Brian Henderson, at the University of Southern California, obtained preliminary data that support an important association between the CYP17 gene and breast cancer risk. This gene encodes an enzyme that functions at key points during the synthesis of estrogens in the ovaries. It contains a polymorphism, or change in the DNA sequence, which results in two alleles, designated A1 & A2. Thus, there are three different combinations of the gene that a woman can have: A1/A1, A1/A2 or A2/A2. Dr. Henderson found an increased risk of advanced breast cancer in women who carried the A1/A2 or A2/A2 form of the CYP17 gene. A2 women were two and one-half times more likely to have advanced breast cancer than A1/A1 women. It was also found that CYP17 is associated with age at menarche (the age when a woman first starts ovulating and having menstrual periods). The importance of these findings is twofold: 1) the CYP 17 A2 forms may play a role in as much as 30% of all breast cancer, and 2) the three forms of the CYP 17 gene (i.e., the "genotype") may be an important marker for the onset of ovulation and the establishment of regular ovulatory cycles (which may be the most critical reproductive determinant of breast cancer risk). A colleague of Dr. Henderson's has received BCRP funds for another project to verify these findings, and to look for possible differences in the distribution of these alleles among groups of ethnically diverse women.
Dr. Shelley M. Enger at the University of Southern California, conducted a two-year study (Alcohol and Risk of Estrogen-Receptor Positive Breast Cancer) to investigate whether the relationship of alcohol consumption and risk of breast cancer is distinct between women with estrogen-receptor positive (ER+) and those with estrogen-receptor negative (ER-) tumors. She found that consumption of 27 grams of alcohol per day (approximately 2 or more drinks) was associated with an increased risk of ER+ and PR+ breast cancer and that alcohol intake is related only to hormone-receptor positive tumors, supporting an estrogen-mediated effect of alcohol on the development of breast cancer. And although the issue is not yet resolved, fairly substantial epidemiologic and clinical evidence suggests that hormone-receptor status defines distinct tumor types, and her findings provide further support for this hypothesis.
Bovine Leukemia Virus and Human Breast Cancer Risk. Dr. Gertrude Buehring of University of
California, Berkeley completed a 1-year IDEA project in which she found evidence that human samples (breast biopsy/blood serum) showed the possibility of a prior infection with a virus, Bovine Leukemia Virus (BLV). A similar virus is known to cause breast cancer in mice. Although there is no present evidence that BLV directly causes human breast cancer, the precise risk that may be associated with the consumption of undercooked beef or unpasteurized dairy product has not been rigorously determined. Dr. Buehring's lab has additional BCRP funding to explore this topic in more detail using the methods of molecular biology. The potential of foreign infectious agents to cause human disease is of interest, and represents a highly novel approach in searching for the potential environmental causes of and/or risks associated with human breast cancer.
Dr. Nicole M. Probst-Hensch of the USC/Norris Comprehensive Cancer Center, in a one-year study of women of different ethnic backgrounds (Breast Cancer and Genetic Differences in Estrogen Formation), looked into the question of whether postmenopausal women differ genetically in how efficiently their aromatase enzyme produces estrogens, and whether such differences affect breast cancer risk. (Aromatase is the protein most relevant for estrogen production in humans and is the rate-limiting step in converting the androgen androstenedione to estrogen.) She looked at two variations (polymorphisms) of the gene for aromatase, and found that genetic variation at either of the two known loci does not appear to directly influence the efficiency with which aromatase converts precursor hormones into estrogens. Other work (in a very small sample) showed that, while African-American women had higher concentrations of androstenedione hormones in the blood than Latina women, Latina women produced estrogens more efficiently for any given amount of androstenedione than African-American or White women.
This suggests that other, as yet unknown, variations may be responsible for the obscured differences. However, these potential differences in aromatase activity do not correlate with the differences in postmenopausal breast cancer risk of these ethnic groups. Her work is important given that medications that specifically inhibit aromatase function in the breast are currently being developed. Therefore, her work needs to be followed up to establish whether differences in the androstenedione to estrone ratio reflect genetic variation in the aromatase gene at loci other than the two already studied, and whether they are of relevance to breast cancer risk, and to confirm whether elevated local or systemic aromatase activity exists in a subgroup of woman who could potentially benefit from preventive treatment with aromatase inhibitors.
Environment and gene/environment interactions: nature and nurture
Several BCRP projects were funded to identify and characterize agents that could cause or contribute to the development of breast cancer.
Dr. Moire R. Creek of SRI International is investigating whether xenoestrogens (environmental estrogens) can cause DNA damage to breast cells. She is finding that the status of the estrogen receptor in the cells may influence the amount of detectable DNA damage. Dr. Regine Goth-Goldstein at Lawrence Berkeley National Laboratory is looking at breast cancer susceptibility by concentrating on two enzymes, one that activates (CYP1A1) and the other that detoxifies (GSTM1) carcinogens called polycyclic aromatic hydrocarbons. She finds a trend, which is not yet statistically significant, of a higher percentage of breast cancer patients lacking the detoxifying gene.
Some proteins can serve as predictors of breast cancer development and progression. Understanding how known markers function in normal and tumor cells and identifying new markers can provide us with ideas regarding what aspects of cell growth and development should be targeted for therapy. Dr. Donna Williams-Hill of University of Southern California is investigating the role of tumor suppressor gene expression during different stages of rat mammary gland development in conveying breast cancer susceptibility. Dr. Williams-Hill has shown that BRCA1 protein levels are lowest in the mammary gland of 3-week old rats and increase gradually as the rat ages to 5 weeks (pre-puberty) and 8 weeks (puberty). Continued experiments will determine whether susceptibility to carcinogen exposure correlates with BRCA1 levels.
Hormones and nutrition: understanding the modern woman's lifestyle
Recently an additional form of the estrogen receptor (ER) was discovered and named ERb. Dr. Peter Kushner of University of California, San Francisco has found that ERb signals in opposite ways from the traditional ER (ERa) when bound with AP-1 and 17a-estradiol: ERa turns on genes and ERb turns off genes. However, the interaction of the antiestrogens tamoxifen, raloxifene, and ICI 164384 with ERb at an AP1 site turns genes on. Thus, an increase in the population of ERb may be responsible for the development of antiestrogen resistance.
Dr. James Felton of Lawrence Livermore National Laboratory is looking at the metabolism of PhIP, a carcinogen that can be generated by cooked meats. He is developing a method to detect the PhIP metabolites in human urine after having successfully detected them in rat urine. The ultimate goal of this project is determine the metabolite profile that is associated with DNA adduct formation and breast cancer susceptibility.
Recently Initiated Research
In 1997, BCRP awarded 14 new grants to investigate possible causes of breast cancer, including exploration of various pesticides, gene/environment interactions, detection of a viral infection contracted through cows, and exposures of flight attendants. For example, one study is exploring the interaction between genetic variation in how certain toxins are handled by the body and breast cancer risk. The results should make a significant contribution to the current knowledge about possible environmental causes of breast cancer. Other studies are examining the possible link between breast cancer and various environmental factors, including radiation, ozone, and viruses.
Prevention: Eliminating the Danger of Breast Cancer
Research on the causes of breast cancer provides a basis for prevention and early detection efforts. Likewise, research on prevention often provides tantalizing clues to etiology.
- Research Conclusions
- No projects on prevention were completed in 1997.
- Research in Progress
- Explaining nutritional pathways for prevention of breast cancer
Dr. Nurulain Zaveri of SRI International is developing novel chemopreventative synthetic drugs based on the structure of a compound found in green tea, epigallocatechin-3-gallate. Drugs derived from natural products have a strong appeal and a potential safety advantage over more conventional drug options. Dr. Marcia Dawson, also of SRI International found that natural retinoids do not synergize with Vitamin D; however, she has found that three retinoids, which inhibit the formation of new blood vessels, cause the death of both estrogen-dependent and estrogen-independent breast cancer cells.
Active lifestyle modification: what women can do
Dr. Catherine L. Carpenter, in her study of the impact on hormones and breast cancer risk has described the effect of lifetime physical activity on the risk of developing breast cancer after menopause. She found that women who exercised at least 13 years with duration of more than four hours per week, were almost 30% less likely to develop breast cancer than women who did not exercise. Exercise intensity and duration was also summarized prior to age 40, and age 40 or older. Women who engaged in vigorous activity (examples: aerobics, field hockey, jogging) on the average three hours or more per week from menarche until age 40, and age 40 or older were almost 50% less likely to develop breast cancer than women who were sedentary throughout their lives. During the ten years prior to the end of the study, women who engaged in vigorous activity averaging four hours or more per week were 30% less likely to develop breast cancer than women who did not exercise. These results are significant because they indicate a way in which women of all ages can lower their chances of developing breast cancer after menopause, and in particular, these results emphasize the importance of exercise in later years. Another researcher is examining one possible causal explanation of this effect. Dr. Lisa S. Shames and colleagues at the University of Southern California recently observed that moderate exercise may significantly reduce a woman's risk of breast cancer. This reduction may be due to altered ovarian function, specifically, more frequent anovulatory cycles (cycles where an egg is not produced) and/or reduced serum estrogen (and progesterone) levels in ovulatory cycles that likely contribute to a reduced exposure of estrogen to breast tissue and thus reduce the risk of breast cancer.
Recently Initiated Research
In 1997, BCRP awarded one new grant to explore various natural and synthesized retinoids (vitamin A derivatives) as preventive agents for breast cancer.
Early Detection: Improving Survival
Earlier detection of breast cancer is today the best means of reducing breast cancer mortality. Work completed in 1997 includes research exploring new technologies for the detection of breast cancer, as well as research into access and use of existing services by different populations of women.
Research Conclusions
Dr. Erik R. Wisner, at the University of California, Davis, through his study Novel Agent for Lymph Node Imaging & Targeted Gene Therapy has demonstrated a proofofprinciple in the development of a combined diagnostic imaging and therapeutic agent for breast cancer diagnosis and therapy. He developed a prototype diagnostic and therapeutic agent by binding conventional magnetic resonance (MR) contrast materials to lipid microspheres, or liposomes (i.e., microscopically small membrane-enclosed sacs made in the laboratory) that, in preliminary imaging studies significantly improved the visibility of regional lymph nodes on MR images after subcutaneous injection. In addition, they demonstrated significant uptake and expression of marker DNA material in cell cultures exposed to the agent after incorporating the marker into the core of the liposome component.
Dr. Phillip Gardiner at the Northern California Cancer Center, in his study (False-Positive Mammograms: A Barrier to Annual Screening?) found that, contrary to expectations, women who experienced a false positive mammogram slightly increased adherence to screening guidelines. This finding is based on actual screening behavior in the aftermath of a stressful health-related event, and suggests that tailored interventions to prevent these women from being lost to further screening are not necessary.
Dr. Annette E. Maxwell at the University of California, Los Angeles, undertook to better understand factors influencing Filipino women with respect to breast cancer mammography screening (Understanding Breast Cancer Screening in Filipino Women). Her findings with respect to barriers to screening suggest that strategies to increase screening among Filpino-American women should include: Filipino health professionals in interventions; information in Tagalog at local centers and in take-home brochures; involvement of children or other relatives in intervention programs; and providing mammography screening on weekends. Dr. Maxwell, using the data gathered in this study, has obtained a major research grant from the NCI to test an intervention based on her BCRP study.
- Research in Progress
- Developing and improving imaging technologies: better and easier detection
Earlier detection of breast cancer is at present the best means of reducing breast cancer mortality. Work on various technologies to detect breast cancer as early as possible is proceeding. Dr. John Boone at the University of California, Davis is working on improving x-ray detection by changing the design of the detector. Using a thick honeycomb-like structure may enable a greater capture of X rays (and thus more scintillated light to
make the image) while simultaneously reducing the blurring associated with thicker layers of X ray absorption material. Dr. Michael Buonocore of University at the California, Davis is attempting to improve the ability of magnetic resonance imaging (MRI) to distinguish between benign and cancerous lesions (thus reducing the need for biopsies) by modifying the generation and detection of the MR signal. Preliminary results of this IDEA grant have been promising, enabling Dr. Buonocore to obtain a larger grant from the Department of Defense to continue and expand on this work. Dr. Edward Hoffman at the University of California, Los Angeles is attempting to use the potential benefits of nuclear imaging scintillation cameras to distinguish between benign and cancerous lesions in the breast. These cameras are typically very large and, while suitable for whole body work, are ill-adapted to breast imaging. A small, hand-held prototype (using photo-multiplier tubes) able to image portions of the breast has been developed with imaging performance superior to standard cameras; a second, solid state version prototype is now being developed. Clinical studies using the first prototype are now beginning.
Biomarkers and novel screening aproaches: unmasking the hidden signs
Dr. Susan Hawkes at the University of California, San Francisco is finding that a marker called TIMP-3 is present in cancerous tissues but not in normal or benign tissues. TIMP-3 can be detected in the basement membrane of all of the ductal carcinoma in situ (pre-cancers) examined to date, making it an excellent candidate for an early marker of breast cancer. Dr. Christina Niemeyer of The Burnham Institute has found that when a protein called Cripto is present in elevated levels in otherwise normal cells, abnormal outgrowths form. Her experiments show that Cripto does not appear to be involved in the early stages of tumor development but may be involved in tumor progression.
Improving access to screening: reaching every woman
Regardless of the technologies available, women need to make decisions to participate in breast cancer screening efforts. Dr. Jacqueline O'Connor at the University of California, Davis looked at psychological characteristics that motivate breast cancer early detection practices (Benign Breast Biopsy & Cancer Preventive Self-Care). She found that women who had undergone immediate core biopsy of low-suspicion breast lesions detected by mammogram and those that had six-month mammographic follow-up reported greater attention to, and compliance with, recommended breast screening practices, even in the face of increased feelings of vulnerability. Interestingly, those who underwent biopsy reported greater stress levels than those who underwent six-month follow-up, this finding challenging the expectation that the uncertainty attending an extended period of surveillance would result in a higher stress level.
Recently Initiated Research
In 1997, BCRP awarded seven new grants to develop better methods to detect breast cancer, including testing ways to increase use of screening by underserved populations, testing possible markers for cancer in breast tissue, and developing new technologies to improve or replace mammograms. BCRP funded one project to use databases of digitized mammograms to reduce the need for biopsies of non-cancerous tissue. Two projects focus on developing other, non-ionizing detection methods. Another project explores the potential of a biological marker to serve as a diagnostic tool.
Innovative Treatments: Search for the Cure
Finding a cure for breast cancer is one of the most important goals for BCRP. The innovative treatment research projects strive to achieve this goal by taking full advantage of current scientific knowledge to design immunologic and hormonal approaches or new surgical technigues.
Research Conclusions
Dr. Michael Samoszuk of the University of California, Irvine was successful in completing his one-year IDEA grant, Blocking Breast Cancer Progression with Radioactive Antibody. The goal of this project was to
determine whether the presence of a new marker called eosinophil peroxidase would be produced by women's immune response to breast cancer. Dr. Samoszuk's studies showed that more than 80% of breast cancers in women contain abundant deposits of this new marker. An especially notable finding was the presence of large amounts of this marker adjacent to the new blood vessels and connective tissue that support the growth of the tumor. These results are important for the following reasons: 1) they document the presence of a novel breast cancer marker that can be used as a target for therapeutic radioactive monoclonal antibodies, and 2) they suggest that the host immune response to breast cancer may actually play a role in promoting breast cancer growth. The preliminary findings of this study have led to the funding of a Small Business Technology Transfer Grant from the NCI.
Dr. Chung-leung Chan of the University of California, San Diego completed a 2-year Postdoctoral Fellowship entitled EGFR Structure for Drug Design Targeted to Breast Cancer to study the signaling inside breast cancer cells due to growth factor receptors at the cell surface. These growth receptors, EGFR and erbB2, contain amino acid sequences that provide an essential 'tyrosine kinase activity' for signaling functions inside the cell. Dr. Chan introduced mutations in the tyrosine kinase region in order to probe its functional activity. He reported and published that the 3-dimensional orientation of the 'catalytic loop' in the kinase domain was not important, but that the sequence of amino acids was critical for functional activity. These results are initial steps for subsequent drug design efforts to selectively inhibit the growth of breast cancer cells.
In his grant HSP27 Regulation of Breast Tumor Blood Vessel Growth, Dr. Randolph Piotrowicz of The Scripps Research Institute studied the process of blood vessel growth (angiogenesis) necessary to support breast cancer pathogenesis. A key finding was that estrogen caused endothelial cells, which line blood vessels, to increase their production of HSP27. Then, the HSP27 caused a release of a special form of an angiogenesis-stimulating factor (HMW b-FGF) that also directly stimulates tumor cell growth. Further, he was able to localize HSP27 in the endothelial cells and gain information on how its activity could be regulated. This information is applicable to the specific hormonal and cellular environment of breast cancer.
Dr. Anna M. Wu of The Beckman Research Institute of the City of Hope completed a 1-year IDEA project entitled Engineered Antibodies for Imaging and Therapy of Breast Cancer to develop an innovative monoclonal antibody approach to deliver radioisotopes for detection and therapy of breast tumors. The tumor target is based on an antigen, carcinoembryonic antigen (CEA) found in most breast cancers, and the antibodies are actually protein fragments produced by genetic engineering. The so-called 'minibodies' now in development represent a powerful new technology, since they could be used repeatedly for diagnosis and therapy monitoring. These 'minibodies' avoid the immune response that would normally limit their usefulness.
Research in Progress- Immune therapy: mobilizing the body's defenses
Immunotherapy is an emerging field in breast cancer treatment. Breast cancer is not associated with the development of a strong natural immune response as is seen in certain other tumor types (e.g., melanoma). Dr.
Michael Roth at the University of California, Los Angeles is working to enhance the breast cancer patient's own immune response to Her2/neu to determine the regions of the receptor best able to generate a response and the specific cytokines that would be optimal for boosting the immune system. Dr. Thomas Kipps at the University of California, San Diego is developing ways to make the immune system more sensitive to erbB2. He has successfully developed an assay that can detect erbB2 in newly diagnosed breast cancer patients as well as synthetic peptides that can stimulate an antibody-based immune response to erbB2. Dr. Esteban Celis of Cytel Corporation has identified six new peptides targeting HER2/neu, CEA, and MAGE antigens that can be used to develop immune-based peptides. The development of these peptides may make immunotherapy possible for up to 90% of the population. Dr. Malcolm Mitchell at the University of California, San Diego is developing an approach to sensitize the immune system of breast cancer patients to the MUC-1 antibody. He has developed a set of cell culture procedures that will be used to teach the appropriate white blood cells how to recognize the MUC-1 antibody and then select and amplify them. Dr. Joseph Couto of The Cancer Research Fund of Contra Costa is developing novel Ifab2 fragments (pieces of antibodies) that can be conjugated to radioisotopes for targeting breast cancer metastases. He found that in mice the fragments localized to the tumor better than whole antibodies and were cleared from the body just as well. He is now in the process of adapting this system to humans.
New drug design: creative science
Retinoids are agents that have shown some potential in breast cancer therapy. There are a variety of retinoids from different families, with different effects on cell growth. It is therefore important to characterize the actions of
different types of retinoids and choose those that show the most promise for use in breast cancer therapy. The process of narrowing down the choices to a manageable number of agents requires some understanding of how retinoids behave. Dr. Anissa Agadir at The Burnham Institute studies the role of the retinoid acid receptors in breast cancer cell growth. She found that RXR retinoids in combination with RAR retinoids can inhibit the growth and induce cell death in retinoic acid-resistant RAR deficient breast cancer cells. Dr. Magnus Pfahl at the Sidney Kimmel Cancer Center has developed novel retinoids that initiate the process of programmed cell death with 24 hour exposure. He has also found that the new retinoids have a more limited pattern of receptor binding, which differentiates them from the non-apoptotic types of retinoids.
Dr. Francis Markland of University of Southern California is continuing promising studies in mice using a snake venom-derived protein that arrests both tumor growth and spread, which indicates how these processes are related. He is now pursuing gene therapy to produce this snake venom inhibitor directly at the tumor site.
Hormone/chemotherapy targets: improving today's arsenal
Dr. Paul Webb at the University of California, San Francisco is looking at the mechanism of tamoxifen action by examining its interaction with AP-1 (a set of proteins responsible for cell growth and implicated in cancer). He has found that the estrogen receptor (ER) binds to AP-1 in the presence of tamoxifen by way of a "molecular sandwich" in which ER binds the coactivator p160, which binds the coactivator CBP, which binds AP-1. Tamoxifen causes ER to stimulate the activity of p160 component of the sandwich. This cascade partially explains the estrogen-like effect of tamoxifen on cell growth. Recently an additional form of ER was discovered and named ERb.
Dr. Richard Pietras at the University of California, Los Angeles has developed anti-phosphotyrosine proteins targeted against the estrogen receptor (ER) that block ER coupling and, therefore, action. The next step for estrogen to generate a cell response is the estrogen receptor complex must bind to another series of proteins (coactivators) and only then can it turn on the other genes required for cell growth. Dr. Pietras has also found that overexpression of HER2 (which shows some correlation with tamoxifen resistance) regulates the variants of ER differently. Dr. Cara Marks at the University of California, San Francisco is using both monoclonal antibody and biophysical/molecular approaches to study the more external regions of the receptor involved in dimerization. Dr. Marks is working towards a detailed 'map' that shows the ErbB (HER2) domains involved in dimer formation.
Gene therapy and other treatments: new frontiers
Several investigators are looking at ways to improve drug delivery and gene therapy. Dr. John Park at the University of California, San Francisco is using liposomes (microscopically small, membrane-enclosed sacs made in the laboratory) to introduce genes into target cells. For these experiments he is using antibodies that recognize HER2/neu. In test tube experiments, these liposomes can deliver test genes specifically to cells with high levels of HER2/neu, while delivery to cells with low levels of HER2/neu is reduced. The next year of studies will test these observations in animal studies. Dr. Demetrios Papahadjopoulos at the University of California, San Francisco is looking at new ways to deliver drugs to the sites of breast cancer by using targeted, specially designed liposomes in combinations with hyperthermia (heat). He has found a liposome
composition and protocol for combining liposome administration and heat that leads to a two and a half to three fold enhancement of delivery to the breast cancers grafted to mice. These studies lay the groundwork for clinical trials with the newly approved liposomal Doxorubicin. Dr. Orhan Nalcioglu at the University of California, Irvine is investigating the delivery of drugs to the tumor site in combination with use of a contrast agent for magnetic resonance imaging (MRI). He is obtaining critical information on the degree of 'leakiness'
associated with the tumor vasculature in breast cancer. New approaches to understand this 'leakiness' and control it could be important for both optimal detection and therapy options as MRI gains more acceptance.
BCRP also funded grants that are examining the therapeutic properties of other agents. Dr. Robert Stern at the University of California, San Francisco finds that a blood enzyme, hyaluronidase, can neutralize components on the breast cancer cell surface. He is studying how this has an impact on the tumor cell, and finds initial evidence that hyaluronidase will induce apoptosis, make cells susceptible to immune attack, and directly inhibit tumor growth.
Progress has also been made in BCRP grants aimed at improving surgical aspects of breast cancer treatment. Dr. Silvia Formenti at the University of Southern California is developing an alternative to radiation therapy through radiosurgery. Radiosurgery exposes the affected area of the breast to a highly concentrated, precise dose of radiation that can deliver the same dosage in one hour as six weeks of conventional radiation therapy. She has demonstrated that the technique is feasible and has begun to analyze the effects of radiosurgery by treating tumors, removing them and analyzing them for microscopic signs of cell death. Dr. Boris Rubinsky at the University of California, Berkeley is performing pre-clinical studies to optimize cryosurgery for the treatment of breast cancer and to determine the parameters required for complete destruction of the tumor. He has found that mouse tumors that were frozen to 40oC at a rate of 5oC/min still had surviving cells after one freezing cycle. The implication for treatment of human tumors is that multiple freezing cycles would be necessary in order to achieve optimal cell killing.
Recently Initiated Research
In 1997, 16 new grants were funded to investigate innovative treatment modalities, including finding ways to boost the immune system to fight breast cancer; developing methods to deliver genes and/or drugs to cancer cells, and to overcome resistance to drugs; developing drugs to prevent the spread of breast cancer; and exploring ways to tailor therapy to the individual characteristics of tumors. Several studies are exploring different ways to boost the body's immune system to prevent any breast cancer cells that form from developing into an invasive cancer. Some of these studies are developing methods by which the immune system can be augmented or guided to kill tumor cells. Other studies are using new knowledge gained in recent years about the ways in which cancer cells grow and spread to develop new drugs to intervene in the process.
INNOVATIVE CARE: Meeting a Woman's Needs
The method by which research results are communicated and breast cancer therapies are delivered can dictate how sucessful they are. Innovative models of care research projects are finding the best ways to deliver the most advanced treatments to all women, but particularly to those who are often left out of the mainstream health care system.
Research Conclusions
A project (Group Intervention for Women at High Risk for Breast Cancer) undertaken by David K. Wellisch, Ph.D. at the University of California, Los Angeles was an IDEA grant designed to test the feasibility of a new group model (combining aspects of the educational/cognitive behavior and of the dynamic,
social support models) for interventionof women at high risk for breast cancer. He concluded that the basic group model appears feasible to implement with this population with some limitations. The model appears feasible to teach basic nutritional concepts and to reduce some psychological symptoms such as feelings of depression and current anxiety. Some modes of coping can be increased, but the enhancement of venting of emotions appears to require a longer group experience with more total sessions. Grief resolution, a critical issue for this population, appears to also require more group sessions to successfully occur in some key areas. The model appears unfeasible as presently designed to effectively facilitate teaching of appropriate personal risk assessment. With a more intensive, longer group intervention, the majority of the project goals appear feasible, with a substantial reduction in emotional suffering and an increased ability to cope with high risk status possible for this population.
Research in Progress
Dr. Karyn L. Angell, with a Postdoctoral Fellowship Award at Stanford University, is investigating the role of social stress and social support on a woman's delay in seeking treatment for symptoms of breast cancer. Thus far, 25 women have been interviewed and efforts are underway to recruit Latina and Asian women. The results of this study will assist health care workers in identifying and assisting women who are at risk of delaying seeking health care for symptoms of breast cancer.
In another study entitled Determinants of Breast-Conserving Surgery and Survival, Dr. Cyllene R. Morris at California Public Health Foundation is seeking to determine the reasons for the apparent underutilization of breast-conserving surgery in California. Breast-conserving surgery (i.e., lumpectomy as opposed to mastectomy)
with radiation therapy is an equally effective alternative to mastectomy, and was recommended for most women with stage I or II breast cancer by the 1990 National Institutes of Health Consensus Conference. Nevertheless, fewer than 50% of women who are eligible receive breast-conserving surgery in California, even though mastectomies may have profound emotional consequences and do not improve survival rates in women with small tumors. Preliminary findings show that there is a clear trend towards the use of breast-conserving surgery in California. In 1988, breast-conserving surgery was performed in only 31% of women with early stage breast cancer, compared to 54% of women in 1994. The data are also indicating that, in general, women living in poorly educated or in low income neighborhoods are significantly less likely to receive breast-conserving surgery. Further data collection and analysis are underway.
Dr. Janine E. Giese-Davis is receiving postdoctoral training with Dr. David Spiegel at Stanford University. In her project entitled Does change in emotional expression mediate breast cancer survival?, she is trying to determine the specific therapeutic component linking participation in supportive/expressive group therapy to observed differences in disease progression in women with metastatic breast cancer. Past research with supportive/expressive group therapy has shown that survival was extended in metastatic breast cancer patients by 18 months, doubling the survival time of a matched control group (Spiegel et al, 1989). In this project, each woman's emotional expression and talk-time are being coded from videotape as they participate over time in a supportive/expressive intervention for metastatic breast cancer. These measures are being related to survival, physiological, and psychological functioning. The results will help us understand the elements of psychological therapy that can impact a woman's survival with breast cancer.
Recently Initiated Research
In 1997, three new grants were awarded to study innovative methods to deliver care to women with, or at risk for, breast cancer. Two studies focus on developing and delivering interventions to provide critical psychosocial and educational support to groups of women who have difficulty accessing such services rural women and low-income women. A third study is comparing two different ways to deliver screening, diagnosis, and treatment services to underserved populations usual public health system care and care delivered through an integrated, multidisciplinary breast center.
PATHOGENESIS: Understanding the Disease
Breast cancer does not come about as a single event, but rather develops through a series of events, becoming what we diagnose as "cancer" and then gaining increasing degrees of aggressiveness and resistance. Understanding these events is critical to interpreting and intervening in the disease process. Discoveries made in this area are leading to the development of new targets and agents for the treatment of breast cancer.
Research Conclusions
The presence or absence of progesterone receptor has long been used as a predictive marker for prognosis in breast cancer, but its function in breast cancer development is still in question. Dr.G. Shyamala at the
Lawrence Berkeley National Laboratory completed a one-year IDEA grant (Progesterone Action in Human Breast Cancer) to create a model that would allow researchers to explore this question. Dr. Shyamala has identified a cell line that does not form tumors but has significant levels of functional progesterone receptors. As the cells lose their progesterone receptors, they begin to behave increasingly like tumor cells. This research has provided a new model for studying the effects of the presence or absence of progesterone receptors on the generation of the tumor phenotype.
Making genetic distinctions between normal and tumor cells is an important area of investigation in breast cancer research. It is especially beneficial to be able to compare the normal cell genes to the tumor cell genes and determine which ones differ. In his one-year IDEA project New Method for Measuring Breast Cancer Gene Expression, Dr. Daniel Pinkel at the Lawrence Berkeley National Laboratory improved on a technique that examines abnormalities in several genes simultaneously. In this technique, the RNA from populations of normal cells and tumor cells is tagged with different colored fluorescent markers and allowed to compete for a matching sequence that is mounted on a microarray. The cell population (i.e. normal cells) with more of a given gene product will out-compete the cells from the other population (i.e., tumor cells) for a spot on the array. The technique developed by Dr. Pinkel requires fewer numbers of cells to detect differences than those developed by others and, therefore, expands the types of tissues that can used for comparisons.
Dr. Thorsten Heinzel of the University of California, San Diego successfully completed his two-year postdoctoral fellowship, entitled Isolation of Estrogen Receptor Co-factors from Breast Tumors. Dr. Heinzel was awarded this fellowship in order to determine the underlying mechanisms of the estrogen receptor function in the presence or absence of antiestrogen. Previous work has shown that, in order for estrogen to turn genes on or off, it must first bind its receptor. This estrogen-receptor complex must bind other proteins (cofactors) that in turn bind the appropriate DNA sequences. Dr. Heinzel identified novel cofactors SRC/N-CoA and CBP, that serve not only as mediators of estrogen function, but also as mediators for other growth factors or hormones. In addition, he identified a co-repressor, N-CoR, that can bind estrogen receptor in the presence of antagonists. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in mice. The interaction of novel therapeutics with these coactivators and corepressors may provide a new pre-clinical index of the value of breast cancer treatments in individual women.
In her study, Novel Ways to Control the Growth of Mammary Epithelial Cells, Dr. Susanne Koch at the Scripps Resarch Institute has been investigating the processing of the epidermal growth factor (EGF) receptor. The EGF receptor lies at the surface of the cell where it attaches to EGF, which turns on the receptor. One of the ways that a cell turns off a signal from a receptor is to bring the part of the membrane where the receptor is sitting into the cell and degrade the receptor. Dr. Koch has been studying dynamin, a protein that is integral to the process of bringing the receptor inside of the cell. Dr. Koch identified certain proteins that partnered with activated dynamin, and therefore may be involved in regulating the internalization and degradation of the EGF receptor. Dr. Koch resigned from her postdoctoral fellowship in order to take a full-time teaching position.
Dr. Qiang Liu at the Scripps Research Institute, Zinc Finger Proteins to Study Breast Cancer Angiogenesis, was funded to develop a novel class of DNA-binding proteins that target integrin avb3, which is involved in the process of blood vessel formation (angiogenesis). He designed, constructed and characterized two new DNA-binding proteins capable of specifically binding unique DNA sequences. He has shown that these DNA-binding proteins are capable of turning target genes on or off. These DNA-binding proteins are potential tools to treat breast cancer by acting as switches that can turn specific genes such as integrin avb3 on or off. Dr. Liu resigned from his postdoctoral fellowship in order to begin a research career in a biotechnology company.
Dr. Deborah Cadena at the University of California, San Diego completed a two-year New Investigator project entitled ErbB2 and Control of Growth in Breast Cancer Cells. She studied the proteins inside the cell that control the function of two critical growth receptors, ErbB2 and the epidermal growth factor (EGF) receptor. When present, both the ErbB2 and EGF receptors on the cell surface contribute to more aggressive forms of breast cancer. Dr. Cadena studied two regulatory proteins for these receptors. The first protein, SNX1, was found to decrease amounts of ErbB2 and the second, MLD, directly interacts with the growth receptors in the cell membrane also lowering receptor amounts. This research opens up new protein targets, contributing to our understanding of the growth of certain breast cancers.
Dr. Nam Woo Kim at Geron Corporation finished a two-year Research Project. In Telomerase: a Factor for Early Detection of Breast Cancer, he studied a protein that, when present, can make cancer cells immortal and gives them unlimited growth potential. This telomerase protein repairs the ends of chromosomes during cell division. Dr. Kim, in collaboration with researchers at the University of Texas, San Antonio, reported in the Journal of the National Cancer Institute (89:1874-1880, 1997) that telomerase activity is associated with more aggressive tumor behavior. He used a proprietary technology to analyze breast cancer samples with extensive biomarker and diagnostic data for possible correlation with telomerase activity. His published work strengthens the potential for telomerase as a new breast cancer biomarker or target for therapeutic intervention.
Dr. Lisa McPherson at Stanford University was successful in her two-year Postdoctoral project, Estrogen Receptor Regulation in Breast Cancer, which involved the cloning of a critical regulatory protein for the estrogen receptor (ER) gene. The estrogen regulatory factor (ERF-1) cloned in this project is a transcription factor that binds to DNA. Dr. McPherson discovered that ERF-1 is closely related to certain other transcription factors. She is now able to conduct further molecular studies to understand how the ER is regulated in breast cancer cells. More effective therapies against the ER has potential to treat breast cancers in older women.
In his study, Why do 70% of Breast Cancers Metastasize to Bone?, Dr. Jose Millan at The Burnham Institute addressed the issue of cancer cell spread in the body in a one-year IDEA project. His approach was to use a phage display peptide library to discover new receptors on breast cancer cells that could be potential sites for attachment to the bone endothelium. Several promising candidate receptors were found in his mouse system, which will be tested in the future using peptides or peptide derivatives for inhibition of cancer cell spread.
Dr. Hillary Nelson at the University of California, Berkeley completed a one-year IDEA grant entitled Structure of Est-1: a Potential Drug Target for Breast Cancer to develop information on a protein factor that permits the unlimited growth of breast cancer cells. The telomerase enzyme complex repairs the ends of chromosomes after cell division and is present in the majority of breast cancers at a very early stage. A telomerase accessory protein, est-1, regulates telomerase assembly and activity, and could be a target to inhibit cancer cell growth. Dr. Nelson made initial efforts to produce and purify large amounts of est-1 for her studies.
In his study entitled Biology of Telomere Length Conservation in Breast Cancer, Dr. Darryl Shibata at the University of Southern California investigated the activity of the telomerase enzyme with respect to breast cancer progression. Telomerase has gained recent attention in cancer as a target to limit cancer cell immortality in order to arrest tumor growth. In his one-year IDEA project, Dr. Shibata found that telomerase activity is heterogeneous in different areas and cells of a tumor mass, and telomerase activity appears early in breast cancer progression. This project combined both a molecular approach with an emphasis on information derived from clinical material, a valuable multidisciplinary perspective.
Dr. Marian Waterman at the University of California, Irvine in her one-year IDEA project, Proper Relocation of a Tumor Suppressor in Breast Cancer, investigated mechanisms used by breast cancer cells to localize regulatory proteins with the cell. She was particularly interested in the BRCA 1 protein, which when mutated is associated with a high risk for breast and ovarian cancer. Dr. Waterman determined two sites on BRCA 1 that interact with certain cellular localizing proteins. This study also supported the concept that BRCA 1 is a likely tumor suppressor, and these transport proteins target BRCA 1 to the cell nucleus. Further work on cellular transport proteins will be important to reveal how key gene regulatory and tumor suppressor genes function in breast cancer cells.
Research in Progress
Outbreak - how cancer spreads: angiogenesis, invasion, and metastasis
Physical tumor growth is accompanied by recruitment of blood vessels (angiogenesis) as a precursor to the spread of tumor cells to distant sites in the body (metastasis). The specific breast cancer cell surface receptors necessary for spread in the body are being studied by Dr. Jeffrey Smith of The Burnham Institute. His laboratory has found that certain 'integrin' receptors on breast cancer cells are required for metastasis, and is now investigating possible regulatory proteins that control the binding function of tumor integrins. Dr. Alex Strongin at the La Jolla Institute of Experimental Medicine is looking at ways to inhibit metastasis by examining MMP-2 collagenase activation. They found that active collagenase MMP-2 modulates the invasion of tumor cells not only by degrading tissue proteins, but also by masking certain specific cell surface receptors, integrins, by which tumor cells recognize these tissue proteins. They identified the region of MMP-2 that directly interacts with integrins.
Some proteins can serve as predictors of breast cancer development and progression. Understanding how known markers function in normal and tumor cells and identifying new markers can provide us
with ideas regarding what aspects of cell growth and development should be targeted for therapy. Dr. Pierre Desprez at the California Pacific Medical Center looks at the role of Id-1 in breast cancer metastasis. He found that the presence of Id-1 is associated with the invasive phenotype and can cause non-invasive cells to become invasive when Id-1 protein is present. Dr. Daisy De Leon of Loma Linda University examines the role of IGF-II and cathepsin D in tumor metastasis. She asked two questions; do high levels of IGF-II and cathepsin D increase tumor growth and metastasis, and do human breast tumors produce high levels of IGF-II and specific forms of cathepsin D? She found that a distinct form of Cathepsin D is present in high amounts in breast cancer by examining normal and tumor tissues from the same patient.
Too much cell growth: defective messages and internal signaling
Estrogen exposure is strongly associated with the development of breast cancer. Dr. Shiuan Chen at the Beckman Research Institute of the City of Hope has studied how estrogen is produced in fat tissues. He found that cancer-free areas of the breast produce estrogen in lesser amounts than areas of the breast with cancer. He also found that the regulation of estrogen production was under the control of glucocorticoid hormones in cancer-free areas, whereas a protein called cAMP regulated estrogen production in areas with cancer. This study provides evidence that there may be a fundamental difference in how breast tumors are provided with estrogen for their growth when compared with normal breast cells. We know that, in order to function, estrogen must bind to its receptor (ER). Dr. Michael Stallcup at the University of Southern California has found novel protein fragments (GRIP2 and GRIP3) that could be used to block the association of the estrogen receptor with its growth promoting coactivators.
Tamoxifen therapy is commonly used in patients with estrogen responsive tumors. Dr. Myles Cabot at the John Wayne Institute for Cancer Treatment has found that one of the actions of tamoxifen is to block glycolipid metabolism, a biochemical pathway used by the cancer cells to resist Adriamycin therapy, thus supporting evidence that tamoxifen can reverse chemotherapeutic resistance.
Growth of breast tumors is influenced by cell surface receptors that present attractive targets for therapeutic intervention. Basic research on these receptors is still a pre-requisite for developing novel approaches in the future. The Erb2/Her/Neu growth receptors activate genes through intracellular pathways of signal transduction. Dr. Daniel Donoghue at the University of California, San Diego is studying how the critical Neu/Her2 receptor associates as a dimer, which is an active form. He has found protein sequences in the transmembrane domain of Neu/Her2 that are necessary for dimerization. In a separate project, Dr. Gordon Gill at the University of California, San Diego examines the role of sorting nexins, which can control cell growth by degrading receptors. They have found a new sorting nexin (SNX2) that has a different specificity than the SNX1. SNX1 specifically degrades EGF receptors. This means that different sorting nexins can be targeted to different receptors. There is a family of sorting nexins that have similar functions but affect different growth controlling pathways.
In the normal course of events, cells perform their function and then die at the appropriate time a process called programmed cell death or apoptosis. One important way that tumor cells and normal cells differ is that tumor cells do not die off as rapidly as they should. Research examining why tumor cells are deficient in this ability should
eventually lead to discovering ways to cause tumors to reacquire this ability. Dr. Michael Karin at the University of California, San Diego and his Postdoctoral Fellow, Dr. Zheng-gang Liu, are studying the Mitogen Activated Protein Kinase (MAPK) signaling pathways in breast cancer cells. They report that "activation" of the NF-kB transcription factor via tumor necrosis factor (TNF) and MAPKs allows a breast cancer cell to evade programmed cell death. Dr. Jamil Momand at the City of Hope National Medical Center is investigating the loss of p53 function in breast cancer and the ability of a natural inhibitory protein MDM2 to prevent p53 from entering the cell's nucleus to perform its normal functions. Dr. John Reed at The Burnham Institute is investigating how suicide receptors Tumor Necrosis Factor Receptor-Associated Factor (TRAF) proteins transfer suicide signals from TNF receptors into breast cancer cells. He has found that breast cancers downregulate their levels of TRAF-4 suggesting an important change in these tumors that may facilitate their escape from immune surveillance.
Mistakes on the master blueprint: molecular genetics and gene regulation
Dr. Utha Hellmann-Blumberg at the University of California, Davis has found that tamoxifen can be metabolized into a product (4-hydroxy, N-desmethyltamoxifen) that binds to DNA, which is the first step in chemical carcinogenesis, and that this product is detectable in patients taking tamoxifen. Additionally, breast tumors develop resistance to tamoxifen over time and some even become responsive to it. Understanding how tamoxifen interacts with estrogen to exert its effect is crucial for determining the parameters for safe and effective use of tamoxifen, as well as the development of more effective antiestrogens. This line of investigation requires that we also develop an understanding of how estrogen works. Dr. Robert Oshima of The Burnham Institute is investigating a transcription factor Ets2, thought to be capable of switching on or off critical genes necessary for breast cancer progression. He is using transgenic mice as a way to address fundamental questions not approachable using cell lines and tumor samples. On a more global level, breast cancer cells may organize their chromosomes differently than normal cells. Dr. Helene Baribault of The Burnham Institute is using transgenic mice having defective apoptosis regulatory protein Bax, to determine why it appears to be critical for certain therapies for breast cancer in women. Dr. John Reed of The Burnham Institute is devising strategies for enhancing the function of Bax to treat breast cancer.
Searching the unknown: novel breast cancer genes
Breast cancer cells express and regulate their genetic information differently from normal cells. Dr. Michael Press at the University of Southern California is investigating the genes that cause cancer cells to accumulate abnormally large amounts of DNA by finding human gene equivalents to rum1 (the yeast gene that regulates the DNA accumulation). They have found two genes in human cells that qualify as human cousins to rum1. Work is now progressing to determine how these genes function in the cell cycle. Dr. Gregory Shackleford at the Childrens Hospital Los Angeles is identifying genes that are turned on during tumor formation in a mouse model with a predisposition to breast cancer. They are developing a transgenic mouse model that carries two breast cancer genes that are known to cooperate with each other to form tumors (FGF and Wnt) and using the transgenic mice to identify novel genes that cooperate with FGF and Wnt to form tumors more efficiently. So far they have found several genes for factors that cooperate with Wnt in mice and are testing human breast cancers for the activation of these genes. Dr. Terumi Kohwi-Shigematsu at the Lawrence Berkeley National Laboratory is studying proteins from breast cancer cells that organize their chromosomal structure. Her laboratory has found specific matrix organizing region binding proteins specific to breast cancer that could be therapeutic targets.
Unraveling the path to breast cancer: tumor progressionDr. Valerie Weaver at the Lawrence Berkeley National Laboratory is investigating the role of Vitamin D to restore proper communication of breast cancer cells with their microenvironment, and she finds that a specific integrin receptor is necessary for these tumor functions. She can revert tumor cell functions to normal by using specific antibodies to these integrins.
Recently Initiated Research
In 1997, 22 new grants were funded to further understanding of how breast cancer develops, including identifying and understanding the action of genes involved in cell growth control, determining actions of hormones and hormone-blocking drugs, exploring why breast cancer spreads to other parts of the body, looking at effects of vitamins on breast cancer cells, An additional five grants were funded to explore the basic biology of the human breast, including effects of pesticides, repair of genetic damage, and roles of vitamins and hormones on normal breast cells.
The Breast Cancer Research Program employs a systematic process to ensure that the research funded by the Program is unique from, and complementary to, research that is being funded by federal agencies. This process includes the following four steps:
Step 1 Advice on how best to complement research funding available from federal agencies is sought from breast cancer research experts and advocates through means such as the National Advisory Meeting of 1994 and the Advisory Meeting of 1996. The input received at these meetings has resulted in areas of research and funding mechanisms chosen by the Council to encourage applications on breast cancer research issues that are not being well-funded by the federal government.
Step 2 All investigators are required to include in their grant applications the following information about funded research and applications pending with other agencies: the funding agency; the project title; the specific aims of the proposed research project; the dollar amount and duration of funded and pending grant requests to other agencies; the percentage of the investigator's effort devoted to the project; and a desciption of any potenial overlap with the study proposed in the BCRP application and what changes will be made to eliminate overlap should BCRP fund the grant. This information is verified by the Contracts and Grants Officer at the applicant institution.
Step 3 All applications are scored by review committees on the degree to which the research proposed is innovative. This score is a component of the overall score for all grant applications. In addition, peer reviewers are asked, as part of their application evaluation, to note any actual or potential overlap between the proposed research and other research being conducted or planned by any investigator. If proposed projects are found to overlap significantly with currently-funded research, they either are given a poor scientific merit score (because innovation is an element of this score) or are asked to modify the proposed study to remove overlapping elements. Reviewers are selected in part because of their knowledge of research being conducted throughout the nation, so they are also in a position to note whether the proposed research is truly innovative and unique.
Step 4 Once the grants to be awarded have been chosen, Program staff carefully review several administrative aspects before releasing funds. One of these aspects is potential duplication with other studies. Staff review the information described above, as well as grants being funded by the National Cancer Institute and the Department of Defense. If any actual or possible overlap is identified, the investigator is asked to either provide further information concerning the funded projects, or is asked to delete portions of the proposed work to eliminate such overlap. Program staff must be satisfied with the resolution before funds are released.
The primary federal agencies funding research on breast cancer are the National Cancer Institute (NCI) of the National Institutes of Health (NIH), and the U.S. Department of Defense (DOD) Breast Cancer Research Program. In 1997, the NCI expended $373,912,050 in extramural breast cancer research support, and the DOD distributed $123,753,891 in breast cancer research funds. The relative distribution of funds across areas for these two programs, as compared to the BCRP, is shown below.
Category
- NCI 1997
- Grants
- $ %
- of Total
- DOD 1997
- Grants funded
- $ %
- of Total
- BCRP 1997
- Grants
- $ %
- of Total
Normal Breast Biology $3,409,455 0.9 $1,282,433 1.0 $808,427 5.5 Breast Cancer Biology $83,976,646 22.5 $30,885,919 25.0 $4,995,153 33.9 Epidemiology $93,296,889 25.0 $3,282,654 2.7 $2,776,485 18.8 Early Detection $23,912,247 6.4 $6,566,759 5.3 $411,100 2.8 Treatment $94,635,780 25.3 $78,318,280 63.3 $4,343,518 29.5 Prevention $39,125,891 10.5 $995,302 0.8 $967,300 6.6 Cancer Control and Survivorship $29,056,453 7.8 $763,655 0.6 $431,183 2.9 Public Health/ Professional Education $6,498,689 1.7 $1,658,889 1.3 0 0 TOTAL $373,912,050 100 $123,753,891 100 $14,733,166 100
- The BCRP invested a greater proportion of funds into investigating the biology of breast cancer, with nearly half of this amount invested in specific areas identified by the Council as crucial, yet under-funded areas the biology of the normal human breast, the effects of possible causative agents, and new experimental models to study breast cancer.
A large investment of BCRP funds was made in epidemiology, with almost all of the funded studies focusing on environmental and/or chemical causes of breast cancer. This is in contrast to DOD, which invested a very small proportion of funds in this area, and NCI, for whom diet and nutrition was the most well-funded topic in this area.
In early detection, the Program has in past years devoted significant funding in three main areas: development of innovative, new methods and technologies; improvement of existing technology (mammography); and social/behavioral research on access and use of screening. The Council remains interested primarily in the first area and continues to encourage funding that will result in better and more effective early detection.
Over the past three years, the program has gradually increased funding in research on breast cancer treatment. However, the Program has filled a unique niche in this area. While NCI supports large clinical trials of new chemotherapy, BCRP has focused on small pre-clinical or pilot studies of new approaches to therapy.
The Program placed a higher priority on issues that were receiving less funding from federal agencies and which are of particular interest
in our state.
The ultimate challenge for all agencies engaged in the fight against breast cancer is prevention. The gap in knowledge about the basic biology of the normal breast and the causes and development of cancer limit current efforts. By virtue of a targeted call for applications in this area, BCRP was able to fund nearly as much research on prevention in California as the much larger DOD program funded across the country. Continued targeting of this area is expected to sustain this level of funding and to bring results in more basic research to bear on breast cancer prevention quickly.In this, the third funding cycle, the California Breast Cancer Research Program has further expanded the range of breast cancer research being performed in the state. The Program placed a higher priority on issues that were receiving less funding from federal agencies and which are of particular interest in our state, especially prevention, chemical and environmental causes of breast cancer, the biology of the normal human breast, and new, innovative treatment modalities. The Program has also increased emphasis on collaboration, translation, and community involvement by creating specific award types that stimulate and support these concepts. Finally, BCRP also invested over $3 million to specific topics that have not been sufficiently supported by these other agencies namely basic breast biology and prevention, risk identification, and reduction. It is also important to note that a number of BCRP's Cycle III grants focus on populations of special interest to California (e.g., racial and ethnic
populations with large numbers of California residents). By continuing to direct state funds towards important topics in breast cancer that are less supported by federal research dollars and that are of particular importance in the state, the BCRP promises to accelerate progress in reducing the human and economic costs of breast cancer in California.
Research on Women and Minorities
In accordance with statute (AB2055, 1991), BCRP reports on the extent to which state-funded research projects address medical issues of particular concern to women and minorities. Breast cancer is a disease that strikes women almost exclusively therefore all research funded by BCRP addresses an issue of particular concern to women. Minority women in general are under-represented in medical research and are underserved in medical practice. BCRP's advisory Council again made research that addresses the needs of underserved women a priority in 1997 because of documented disparities in the morbidity and mortality of breast cancer among these women. Applicants were required to explain how their proposed research would address the needs of underserved women and the reviewers who evaluated grant applications were asked to rate them on this criterion. The Council took this criterion into account in arriving at its recommendations regarding the grants that should be funded.
Of the 66 grants that BCRP awarded in 1997, 33 (50%) were investigations that included human study samples. Women were the sole source of these samples in all of these clinical studies. 23 (35%) of the grants used human tissues or samples, while 12 (18%) used human subjects as participants. Of these 12 clinical studies, five had a major focus on minority or underserved women, while an additional seven studies included, but did not specifically focus on, minority women.
The following five studies had a primary emphasis on minority or underserved women:
- The Breast Cancer Care Center: Innovative Care for the Underserved
- Physical Activity, Diet and Menarche in a Multiethnic Cohort
- Gene-Diet/Tobacco Interactions in Breast Cancer in Asians
- Breast Cancer Risk Factors: Lesbians and Heterosexual Women
- Breast Screening Program in the Hmong American Community
Marion H. E. Kavanaugh-Lynch, M.D., M.P.H. Director
Laurence Fitzgerald, Ph.D. Research Administrator
Katherine McKenzie, Ph.D. Research Administrator
Walter Price, Dr. P.H. Research Administrator
Ivy Savant Administrative Analyst/Graphic Designer
Brenda Dixon-Coby Administrative Specialist
Pattie DiLauro Administrative Assistant
DeShawn Boyd Administrative Assistant
Garland Giles Assistant to the Director
The overall objectives, strategies and priorities of BCRP are set by the Breast Cancer Research Council, which actively participates in overseeing the program and making final recommendations on the research projects to be funded. In each Grant Cycle, BCRP awards grants based on the Council's recommendations, which are based on peer reviewers' evaluations, program priorities and available funds.
The council currently consists of 16 members: five representatives of breast cancer survivor/advocacy groups; five scientist/clinicians; two members from non-profit health organizations, one practicing breast cancer medical specialist, two members from private industry, and one ex-officio member from the DHS Breast Cancer Early Detection Program.
Council members are appointed by the University, drawn from nominations submitted by Council members, individuals, institutions and agencies throughout the state.
About the Council
| 1996 - 1997 Chair and Vice Chair |
Carol J. Voelker, Ph.D., was appointed to the BCRC in July, 1995, as a representative of a non-profit health organization. A sixteen year member of Soroptimist International of the Americas, whose focus in the health area is breast cancer awareness, Dr. Voelker is also a member of the National Breast Cancer Coalition and the Orange County Chapter of the Susan G. Komen Breast Cancer Foundation. She also works as a legislative advocate to obtain funding at both the state and national levels for breast cancer research.
- Carol L. MacLeod, Vice Chair
- July 1, 1995 - Nov. 7, 1997
Carol MacLeod, Ph.D. (Scientist/Clinician Representative), is a Professor of Medicine at the University of California, San Diego, Associate Director of the UCSD Cancer Center. She serves as Leader of the Cancer Genetics Program, and she co-directs a National Institutes of Health Cancer Training Grant. She has served on National Institutes of Health Scientific Review Panels for Cancer Centers and Research Grants. She is currently a member of a Scientific Advisory Panel for the American Cancer Society. She holds research grants from the National Institutes of Health, the Susan Komen Foundation, the Clayton Foundation and the California Research Coordinating Committee to support her active research program. Her research focuses on the regulation of gene expression in tumor cells and the induction of tumor cell differentiation. Using both cell and molecular biology, her laboratory examines the mechanisms regulating gene expression. Several unique genes identified in a search for tumor related genes are now being assessed for their possible role in tumor formation and dissemination using gene targeting and transgenic approaches.
| 1997 - 1998 Chair and Vice Chair |
Mr. Erwin (Industry Representative), is a founder and serves as President and Chief Executive Officer of Biosource Technologies, Inc., founded in 1987. As a co-founder of Sungene Technologies Corporation, he served as Vice President of Research and Product Development from 1981 through 1986. Mr. Erwin has served on the Biotechnology Industry Advisory Board for Iowa State University and the Executive Committee of the California Tissue Culture Association. He is currently a Director of the Independent Institute, the Marti Nelson Cancer Research Foundation and Large Scale Biology Corporation. Mr. Erwin's biotechnology experience includes research in molecular biology at Abbott Laboratories and at the University of Alabama Medical School. He received his M.S. degree in genetics from Louisiana State Universit
- Suzette Wright, Vice Chair
- July 1, 1996 - June 30, 1999
Suzette Wright, M.S.P.H., is a five year survivor and advocate of breast cancer. As a member and current vice president of Save Ourselves/Y-ME Breast Cancer Organization in Sacramento, she was active in lobbying and testifying for the Breast Cancer Act of 1993. Suzette balances her advocacy work with teaching mathematics at the Learning Skills Center at UC Davis and spending time with her family. She strongly hopes that her twenty one year old daughter will never personally experience breast cancer.
Advocates |
- Floretta Chisom
- August 27, 1997-June 30, 2000
- Floretta Chisom brings her many years of experience in committee work and team building to the BCRC. She is currently the Director of Health and Human Services for Oakland CA. She also serves on a variety of health and social service committees such as the Healthy Start Advisory Board; the City of Oakland Commission on Homelessness; the City of Oakland Health Commission; the Community action agency advisory board; and the Ann Martin Children's Center. She became active in the fight against breast cancer as a member of the Breast Cancer Fund Board. The welfare of her daughter provides Ms. Chisom with her strong motivation for eradicating breast cancer.
- Arlyne Draper
- July 1, 1996 - June 30, 1999
Breast cancer has been a part of Arlyne and her family's lives for the past 20 years. Arlyne Draper has survived two breast cancers and, for the past five years, has dedicated herself to fighting this disease by promoting education, increasing awareness, and encouraging others to speak up and demand attention. She is founder of the Women's Cancer Task Force (WCTF), a grassroots organization and a chapter of Y-ME, which works for changes in breast cancer education, research, diagnosis and treatment. She also co-founded the California Breast Cancer Organizations (CABCO) where she serves as president and representative to the National Breast Cancer Coalition (NBCC) working board. She has participated in numerous breast cancer conferences and committees at the state and federal levels.
- Andrea Martin
- Feb. 15, 1994 - June 30, 1997
Andrea Martin is a breast cancer survivor and advocate who, in 1993, founded The Breast Cancer Fund, a national nonprofit organization that raises awareness and funding for innovative research, education, patient support and advocacy projects. Ms. Martin participated in the drafting and passage of the Breast Cancer Act of 1993 and was appointed to the BCRC. She also serves on the Advisory Council to the Department of Health Services, which oversees the Breast Cancer Early Detection Program.
- Carol Pulskamp
- July 1, 1995 - June 30, 1998
Carol Pulskamp is a life-long activist and (since 1990) breast cancer survivor/advocate. She is a former educator of the deaf, and a staunch and outspoken advocate for health care reform, rights of disabled persons, etc. She is a founding member and the executive director of the Northern California Coalition for Cancer Survivorship, an association member of the National Coalition for Cancer Survivorship.
- Beverly Rhine
- July 1, 1996 - June 30, 1999
Beverly Rhine is a breast cancer survivor and vice president of the Women of Color Breast Cancer Survivors Support Project. She is dedicated to providing support, counseling and psycho-social assistance to African American women faced with breast cancer. Beverly is also a member of the Breast and Cervical Cancer Early Detection Program Advisory Council.
Ex-Officio Members |
- Jacquolyn Duerr, Alternate Member
- Feb. 15, 1994 - Ongoing
Jacquolyn Duerr, M.P.H. is Chief of the Breast Cancer Early Detection Program in the Cancer Control Branch of the California Department of Health Services. In this position, she is responsible for the design and development of a statewide program for the expansion of breast cancer screening services to low-income, underserved, older women. She has overseen the creation of local partnerships comprised of providers and consumers to create a network for case management, and to monitor and improve the quality of these services. She has extensive training and experience in community health education and outreach.
- Liana Lianov
- Feb. 15, 1994 - Ongoing
Liana Lianov, M.D., M.P.H. is currently medical advisor to the Cancer Detection Section at the California Department of Health Services. Over the past seven years, she has developed and implemented the Breast and Cervical Cancer Control Program, which is federally funded, and the Breast Cancer Early Detection Program, which is funded by 50% of the tobacco tax raised by the Breast Cancer Act. These programs offer screening, diagnostic and educational services to low income women. Dr. Lianov is a physician board certified in both Internal Medicine and Preventive Medicine and Public Health and was trained at Good Samaritan Medical Center in Phoenix, Arizona and Baylor Medical Center in Dallas, Texas. She received her Masters Degree in Public Health from the University of California, Berkeley in 1990 and her medical degree from the University of Nevada in 1985.
Industry |
Marco M. Gottardis- March 3, 1996 - June 30, 1999
Marco M. Gottardis Ph.D. is a Research Investigator in the Dept. of Endocrine Research at LIGAND Pharmaceuticals in San Diego, California. His research group is currently developing new classes of breast cancer hormonal therapies (which include novel retinoid and anti-hormonal agents) that have greater target selectivity and less side-effects than current days. Dr. Gottardis has studied the molecular and biological mechanisms of resistance to breast cancer hormone therapies for the last 15 years. He has trained in several of the preeminent breast cancer research laboratories. He serves on several standing and ad hoc research grant study sections for the American Cancer Society, U.S. Army Breast Cancer Research Program and National Institute for Environmental Health Sciences.
| Medical Specialist |
- Bobbie Head
- Jan. 15, 1997 - June 30, 2000
Bobbie Head, M.D., Ph.D. specializes in caring for women with breast cancer in her private practice in Marin County, California providing education and information to women who have been diagnosed with breast cancer. Her practice caters to the emotional, physical and spiritual needs of women and provides access to complimentary care modalities to assist women with making informed decisions about treatment options. Dr. Head chairs the Breast Health Committee at Marin General Hospital and the California Healthcare Systems Science Committee, which evaluates new trials for 3 Bay Area Hospitals. She also serves on the Board of Directors of the Hospice of Marin. Bobbie Head is active in clinical research and teaching and she participates in national and pharmaceutical company trials that utilize new cancer therapies.
| Non-Profit Health Organizations |
Lisa Bailey- Feb. 15, 1994 - June 30, 1997
Lisa Bailey, M.D. is a breast cancer surgeon on the staff of Summit Medical Center, Alta Bates Medical Center, and The Surgery Center, and is an Assistant Clinical Professor at the University of California, Davis. She is president-elect of the American Cancer Society, California Division and past president of the Alameda County Unit. A nationally recognized leader in surgical oncology, she has served as an advisor for the Institute of Medicine and for Donna Shalala's National Breast Cancer Summit (1993), and locally serves on the Alta Bates Medical Center Comprehensive Breast Center Professional Advisory Committee, the Northern California Cancer Center Advisory Board and Breast Cancer Committee, and co-founded the Bay Area Tumor Institute tumor board.
- Judith Luce
- August 12, 1997 - June 30, 2000
Judith Luce has demonstrated her dedication to the fight against breast cancer in her volunteer and her professional work. She has been an active member of American Cancer Society for over 15 years. She has served as president of the San Francisco Unit of the ACS, as well as both member and Chairperson of the California Division Breast Health Task Force. Dr. Luce is a faculty member at UCSF and the director of Oncology Services at San Francisco General Hospital. She is also the principal investigator on several clinical trials including a study on breast and cervical cancer intervention, and a multi-center breast cancer prevention trial. Her proudest achievement of her volunteer/research life has been her work with others in the Department of Public Health to offer breast and cervical cancer screening to underserved women in San Francisco. "We started this work in 1988, and today have highly successful programs in BCCCP (we were one of the first in the state) and BCEDP, as well as a new program to do targeted outreach to every woman in our patient population who has not been screened. We have worked with a variety of others to accomplish this, and I am certain that we are seeing the results of these efforts in better health for women in our city."
| Scientist/Clinician |
- Shelley Adler
- July 1, 1996 - June 30, 1999
Shelley Adler is a medical anthropologist specializing in sociocultural gerontology at the University of California, San Francisco. Some of her current research includes "Women's Breast Cancer Treatment Choices by Cohort and Ethnicity;" "Older Women's Interactions with Their Physicians Regarding Breast Cancer;" and "Alternative Breast Cancer Treatments." She is a member of the American Anthropological Association, the Society for Medical Anthropology and the American Society on Aging.
- J. Patrick Fitch
- May 1, 1995 - June 30, 1997
J. Patrick Fitch, Ph.D. is Director of the Center for Health Care Technologies in the Biology and Biotechnology Research Program at Lawrence Livermore National Laboratory. He currently oversees the development and management of all health care-related projects at LLNL, which include over 40 projects in diagnostics, treatment and information systems. His own research includes the development of new surgical tools and catheter-based systems. These projects involve close collaboration with clinicians, industry and researchers in the breast cancer field, as well as other fields.
- Susan M. Love,
- July 1, 1996 - June 30, 1999
Susan M. Love, M.D. is an author, teacher, surgeon, researcher and activist. She is an Adjunct Professor of Surgery at UCLA and former Director of the Revlon/UCLA Breast Center. She is one of the co-founders of the National Breast Coalition and serves on their Board of Directors. She also serves as a co-chair of the Biological Resources Task Force of the National Action Plan on Breast Cancer.
- Maria Pellegrini
- July 1, 1996- June 30, 1999
Maria Pellegrini, Ph.D., is currently Dean of Research in the College of Letters Arts and Sciences at the University of Southern California in Los Angeles. Dr. Pellegrini's research interests have included studies of the structure-function relationships within proteins and the regulation of gene expression. She is the recipient of an Alfred P. Sloan Foundation Fellowship and a Dreyfus Foundation Teacher-Scholar Award and has received several research and training grants from the National Institutes of Health. Since 1977, Dr. Pellegrini has been Professor of Biological Sciences at USC. Dr. Pellegrini has served on a number of National Institutes of Health grant review panels, including a current assignment on the NIH Training Grant Study Section. She is a breast cancer survivor and a co-founder of Reprogen, Inc., a biotechnology company focused on developing new products relating to women's reproductive health.
- Anne Wallace
- August 27, 1997 - June 30, 2000
Anne Wallace, M.D., has substantial experience with breast cancer patients, basic research, and clinical research. She is a surgeon at the University of California, San Diego whose practice consists primarily of breast cancer patients. Dr. Wallace has experience in research at many levels. She heads the National Surgical Adjuvant Breast and Bowel Project (NSABP) for UCSD, a large scale clinical study that has increased in efficiency and in the patient participation under her direction. She is a member of the UCSD Cancer Center Protocol Review Committee, which is a body that evaluates the protocols for grant applications from the entire Cancer Center. She also collaborates on research projects that investigate the basic biology of breast cancer. She has a profound interest in funding forward thinking research that is maximally beneficial to breast cancer patients.
Summary of Awards by Institution
|
Duration (Years) | Direct Costs | Indirect Costs | Total Costs |
|
2 | $200,000 | $152,000 | $352,000 |
|
1 | $50,000 | $47,500 | $97,500 |
|
2 | $70,000 | $5,600 | $75,600 |
|
2 | $70,000 | $5,600 | $75,600 |
|
2 | $149,000 | $141,550 | $290,550 |
|
2 | $200,000 | $190,001 | $390,001 |
|
1 | $50,000 | $47,500 | $97,500 |
|
3 | $311,996 | $294,021 | $606,017 |
|
2 | $200,000 | $190,000 | $390,000 |
|
2 | $70,000 | $5,600 | $75,600 |
|
3 |
|
|
|
|
1 | $78,879 | $7,843 | $86,722 |
|
2 | $199,996 | $93,387 | $293,383 |
|
2 | $149,842 | $44,153 | $193,995 |
|
1 |
|
|
|
|
3 | $210,790 | $255,055 | $465,845 |
|
2 | $150,000 | $64,200 | $214,200 |
|
1 | $72,699 | $20,719 | $93,418 |
|
1 | $50,000 | $24,000 | $74,000 |
|
2 | $110,000 | $86,900 | $196,900 |
|
2 | $149,998 | $90,214 | $240,212 |
|
2 | $69,999 | $0 | $69,999 |
|
2 | $70,000 | $0 | $70,000 |
|
2 | $150,000 | $90,996 | $240,996 |
|
2 | $70,000 | $0 | $70,000 |
|
2 |
|
|
|
|
1 | $20,862 | $3,129 | $23,991 |
|
2 | $199,917 | $71,171 | $271,088 |
|
2 |
|
|
|
|
1 | $49,830 | $7,092 | $56,922 |
|
2 | $195,638 | $183,409 | $379,047 |
|
2 |
|
|
|
|
2 | $70,000 | $5,600 | $75,600 |
|
3 | $305,071 | $224,078 | $529,149 |
|
2 | $197,038 | $145,758 | $342,796 |
|
1 | $49,950 | $37,463 | $87,413 |
|
2 | $154,816 | $112,475 | $267,291 |
|
1 | $74,360 | $55,770 | $130,130 |
|
2 | $70,000 | $5,600 | $75,600 |
|
2 |
|
|
|
|
2 | $200,000 | $186,800 | $386,800 |
|
2 |
|
|
|
|
1 | $37,500 | $10,361 | $47,861 |
|
1 | $37,750 | $21,904 | $59,654 |
|
2 | $70,000 | $5,600 | $75,600 |
|
2 |
|
|
|
|
2 | $150,000 | $0 | $150,000 |
|
2 | $150,000 | $0 | $150,000 |
|
2 | $69,981 | $0 | $69,981 |
|
1 |
|
|
|
|
3 | $322,374 | $0 | $322,374 |
|
2 | $149,935 | $0 | $149,935 |
|
2 | $70,000 | $0 | $70,000 |
|
2 |
|
|
|
|
1 | $75,000 | $0 | $75,000 |
|
2 | $193,224 | $0 | $193,224 |
|
2 |
|
|
|
|
1 | $31,943 | $0 | $31,943 |
|
1 |
|
|
|
|
2 | $197,564 | $0 | $197,564 |
|
2 | $150,000 | $96,781 | $246,781 |
|
2 | $69,519 | $5,562 | $75,081 |
|
1 | $74,608 | $48,464 | $123,072 |
|
2 | $148,531 | $93,272 | $241,803 |
|
2 | $70,000 | $5,600 | $75,600 |
|
3 | $771,749 | $501,533 | $1,273,282 |
|
2 | $208,989 | $104,581 | $313,570 |
|
3 | $455,234 | $295,848 | $751,082 |
|
2 |
|
|
|
