Sulfotransferase isoform 1A1 (SULT1A1) is a Phase II xenobiotic metabolizing enzyme that catalyzes the sulfation of a host of structurally diverse endo- and xenobiotics, including tamoxifen (TAM) and raloxifene (RAL), therapeutic agents used in breast cancer prevention and adjuvant therapy. We have shown that a common genetic polymorphism in SULT1A1 that confers low enzyme is associated with poor overall survival in tamoxifen-treated breast cancer patients. Because SULT1A1 sulfates the active metabolites of TAM and sulfation is generally considered to be a detoxification/elimination pathway, these results did not support our original hypothesis that rapid SULT1A1 activity would be associated with poor overall survival in patients receiving TAM adjuvant therapy. Subsequent studies, however, demonstrated that sulfated TAM metabolites are potent inducers of apoptosis in breast cancer cell lines. We have also shown that over-expression of SULT1A1 in cell lines enhances the apoptotic-inducing effects of RAL. The long-term objectives of this project are to elucidate the factors, both genetic and epigenetic, that dictate SULT1A1 activity in breast tumor cells and to validate SULT1A1 expression in breast tumors as a biomarker of therapeutic response. To achieve these objectives, we propose to: (1) examine the influence of epigenetic factors on SULT1A1 expression in normal breast and breast tumor tissues; (2) determine the contribution of genetic variation to differences in SULT1A1 activity; and (3) perform immunohistochemistry for SULT1A1 on a breast tumor tissue microarray and analyze the correlation between SULT1A1 expression, TAM therapy and survival of breast cancer. The newly emerging field of pharmacogenomics will revolutionize the capability of clinicians to predict who will be most likely to respond to a specific therapy. Perhaps more importantly, knowledge of the contribution of genetic makeup to response will allow physicians to predict which patients will not respond and for whom other therapies are advisable. SULT1A1 plays a critical role in the metabolism of many therapies for the prevention and treatment of breast cancer. Understanding the determinants of SULT1A1 expression in breast tissue can ultimately aid decision-making regarding all therapeutic agents that are SULT1A1 substrates. PUBLIC HEALTH RELEVANCE: Genetic variation in SULT1A1, a drug metabolizing enzyme, influences response to tamoxifen therapy for breast cancer. This project is designed to determine the factors responsible for expression levels of SULT1A1 in breast tumors and whether tumor expression levels can predict response to therapy. Such increased knowledge of pharmacogenomics should ultimately make it possible to tailor endocrine therapy to each individual patient.

R01CA128897

2008-05-07

2015-02-28