The Molecular Basis of Inflammatory Breast Carcinoma

Principal Investigator:
Sanford H. Barsky
University of California, School of Medicine, Los Angeles

Co-investigator: Mary L. Alpaugh

Abstract #: A-10

Introduction: Inflammatory breast cancer (IBC) is a poorly understood, little studied form of breast cancer which is very aggressive and particularly devastating in disadvantaged minority women. IBC is characterized by florid tumor emboli within lymphovascular spaces, a phenotype which distinguishes it from other forms of breast cancer. The molecular basis of this phenotype is the focus of this research.

Methods: Using a novel human-scid model of IBC, we have conceptually analyzed this phenotype in three parts.

Results:

1. The tumor cell embolus (IBC spheroid) forms on the basis of an intact and overexpressed E-cadherin / alpha-, beta-catenin axis which mediates tumor cell-tumor cell adhesion analogous to the embryonic blastocyst and accounts for both the compactness of the embolus and its complete dissolution with anti-E-cadherin antibodies, absent calcium, or E-cadherin dominant-negative mutant approaches. Dissolution of the tumor cell embolus by any of these approaches induces apoptosis via an anoikis pathway. The compactness of the embolus results in its resistance to chemotherapy / radiation therapy and its efficiency at metastasis formation and therefore therapeutic strategies which disadhere it are highly desirable.
2. The tumor cell embolus (IBC spheroid), in contrast, fails to bind the surrounding vascular endothelial cells because of complete absence of sialyl-Lewis X/A carbohydrate ligand-binding epitopes on its overexpressed MUC1 which are necessary for binding endothelial cell E-selectin. This natural tumor cell-endothelial cell aversion of the tumor cell embolus (IBC spheroid) further contributes to the compactness of the IBC spheroid and its passivity in metastasis dissemination. Experiments with purified glycosyltransferases which add sialyl-Lewis X/A to MUC1 on the IBC spheroids produce strong electrostatic repulsions which disrupt the E-cadherin homodimers and cause disadherence.
3. The tumor cell embolus finds itself within the vascular lumen in the first place because it stimulates a vascular channel to form around it rather than intravasating into a pre-existing lymphatic or capillary. The enveloping vascular channel does not form from angiogenesis but rather from vasculogenesis as evidenced by experiments where tumor cell emboli (IBC spheroids) are admixed with murine embryonal fibroblasts labeled with green fluorescent protein (GFP) and injected into scid mice. Tumor emboli are observed within lymphovascular spaces where the endothelial cells express vasculogenesis markers as well as endothelial markers. These endothelial cells also express GFP, evidence that they must have formed from the injected GFP-labeled murine embryonal fibroblasts.

Conclusion: The molecular basis of IBC provides a mechanism by which IBC bypasses the traditional steps of intravasation, dissemination and extravasation in its metastatic pathway and affords opportunities for therapeutic intervention.