Regulation Of SULT1A1 In Human Breast
Susan A Kadlubar, Assistant Professor
Environmental & Occupatnl Hlthuniversity Of Arkansas Med Scis Ltl Rock
Grant 1R01CA128897-01A1 from National Cancer Institute, IRG: XNDA
Abstract: 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
Project start date: 2008-05-07
Project end date: 2013-02-28
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Grants awarded to Susan A Kadlubar
Pharmacogenetics Of Hormonal Therapy For Breast Cancer
Susan A Kadlubar, Assistant Professor
Environmental & Occupatnl Hlthuniversity Of Arkansas Med Scis Ltl Rock
Grant 5R01CA118981-03 from National Cancer Institute, IRG: DT
Abstract: Defining genetic factors that predict response to therapy (pharmacogenetics) has the potential of providing important biomarkers of response. The overall goal of this project is to examine the role of pharmacogenetics in the efficacy of adjuvant therapy with the aromatase inhibitor, anastrozole, compared to anastrozole combined with the pure antiestrogen, fulvestrant, for metastatic breast cancer in postmenopausal patients. These agents are relatively new, and pharmacogenetic studies are lacking. We hypothesize that genetic variants in the anastrozole and fulvestrant metabolic pathways, as well as in their molecular targets (the aromatase enzyme and estrogen receptors) will influence therapeutic outcomes. The specific aims of the project are (1) to define the major enzymes responsible for the metabolism of these drugs; (2) to test the hypothesis that functional genotypes in drug metabolizing enzymes are related to the occurrence of treatment-related toxicities, time to progression and overall survival among treated breast cancer patients and (3) to test the hypothesis that intratumoral expression levels of drug metabolizing enzymes influence response to therapy. This study will be performed in the context of an ongoing Southwest Oncology Group-sponsored clinical trial (S0226) and will take advantage of outcome data and biological specimens collected for this trial. We will perform in vitro metabolism studies using human liver tissue fractions and specific recombinant enzymes to identify major metabolic enzymes. We will also genotype for polymorphisms in the identified enzymes, as well as in aromatase and estrogen receptors and in enzymes involved in the production of hot flashes. Finally, using a tissue microarray produced in S0226, we will determine the role of enzyme expression in efficacy of therapy. Backed by the support of the SWOG Breast Correlative Studies Committee, this project will begin to define the role of host genetic variation in response to treatment with anastrozole and fulvestrant in postmenopausal metastatic breast cancer
Project start date: 2006-09-27
Project end date: 2011-07-31