Metabolism of Environmental Chemicals as Breast Cancer Risk
Regine Goth-Goldstein, Ph.D.
Lawrence Berkeley National Laboratory
Analysis of mutations in breast tumors suggests that environmental chemicals such as polycyclic aromatic hydrocarbons (PAHs) might be involved in the development of breast cancer. PAHs are ubiquitous in the environment, and are ingested and inhaled continuously. PAHs act as carcinogens only after being activated in the body. The balance of PAH-activating and detoxifying enzymes determines the amount of binding of PAHs to DNA, which in turn determines the risk of cancer initiation. The activity of these enzymes is determined by genetic and environmental factors. The synthesis of activating enzymes can be induced by PAHs themselves and other environmental toxins, such as dioxin. The interindividual variations in activating and detoxifying enzymes contribute to individual susceptibility to cancer of the lung, colon and bladder. It is proposed to determine if the amount of PAH-activating and detoxifying enzymes in breast tissue represents a risk factor for breast cancer. If this is the case, women with increased susceptibility could be identified and certain preventive measures could be taken, such as more frequent examination, changes in lifestyle to reduce PAH exposure, and possibly changes in diet to alter the activity of PAH-metabolizing enzymes.
These hypotheses will be tested by examining the two major enzymes involved in PAH metabolism: the activating enzyme, cytochrome P4501A1, encoded by the gene CYPlAl, and the detoxifying enzyme glutathione S-transferase, encoded by the gene GSTM1. Variability in the activity of these enzymes is due in part to genetic variation, and in part to modification of gene expression by environmental agents. The presence or absence of the GSTM1 gene, and expression of CYP1A1 will be determined in breast tissue. A collection of about one hundred microscopically nor-mal breast tissue specimens from mastectomy patients or from reduction mammoplasties will be analyzed. CYP1A1 expression (determined by quantitative reverse transcription polymerase chain reaction) and GSTM1 genotype (determined by PCR) will be compared in individuals with breast cancer and healthy individuals. In addition, the correlation of PAH-DNA adduct formation and PAH-metabolizing enzymes will be examined in vitro by treating cells from specimens with different enzyme activity with a model compound and then measuring DNA adducts. These studies should indicate if there is a trend of higher CYP1A1 expression and/or absence of GSTM1 in breast cancer patients.
Final Report (1998)
Analysis of mutations in breast tumors suggest that environmental chemicals such as polycyclic aromatic hydrocarbons (PAHs) might be involved in the cause of breast cancer. PAHs are ubiquitous in the environment, and are ingested and inhaled continuously. PAHs act as carcinogens only after being activated in the body. The balance of PAH-activating and detoxifying enzymes determines the amount of binding of PAHs to DNA, which in turn determines the risk of cancer initiation. The activity of these enzymes is determined by genetic and environmental factors. The synthesis of activating enzymes can be induced by PAHs themselves and by other environmental toxins, such as dioxin. The interindividual variations in activity of PAH- activating and detoxifying enzymes contribute to individual susceptibility to cancer of the lung, colon, and bladder. We have investigated if the amount of PAH-activating and detoxifying enzymes in breast tissue represents a risk factor for breast cancer.
We have examined the activity of the two major enzymes involved in PAH metabolism: the activating enzyme, cytochrome P4501A1, encoded by the gene CYP1A1, and the detoxifying enzyme glutathione S-transferase, encoded by the gene GSTM1. Variability in the activity of these enzymes is due in part to genetic variation, and in part to modification of enzyme level by environmental agents. The presence or absence of the GSTM1 gene, and level of CYP1A1 was determined in microscopically normal breast tissue specimens for breast cancer patients and from healthy individuals. Results from the two groups were compared.
When testing for the presence of the GSTM1 gene in 100 tissue specimens we found that 41% of healthy individuals and 57% of the breast cancer patients lack the GSTM1 gene. Although there seems to be a trend that GSTM1 deletion is more common among mastectomy patients, this difference is not significant.
We have developed a new assay to quantitate the CYP1A1 transcript level relative to the constantly expressed b -actin gene. We have quantified CYP1A1 levels in all epithelial breast tissue material available in the tissue bank. We find a large variation between individuals (400-fold) that is independent of age. The mean CYP1A1 level is higher in mastectomy patients than in healthy individuals, but his difference is not significant. These studies indicate a trend of higher CYP1A1 level and increased absence of GSTM1 in the breast cancer patient group.