Drugs that interfere with the actions of estrogen represent a cornerstone in the treatment of breast cancer, and are important tools with which to study the actions of estrogen in women. These drugs are increasingly effective in breast cancer, but which drug is best for each woman remains unclear. Our work in the first cycle of the Pharmacogenetics Research Network identified, through a series of laboratory and clinical studies, new genetic patterns that predict effects of the estrogen receptor modulator tamoxifen. We now propose to build on these data to examine the influence of an extended series of candidate genes on the effects of the aromatase inhibitor class of drugs and to refine the genetic signatures that predict tamoxifen effects. Our work will involve the following broad specific aims: 1) To identify common genetic variants of the human estrogen receptors and important nuclear coactivators and repressers of these receptors using a combined bioinformatic and direct sequencing approach; 2) To test the hypothesis that these variants alter gene expression or function using in vitro assays; 3) To test the contribution of variants identified during specific aim 1 and 2 to tamoxifen response in the clinical trial of tamoxifen pharmacogenetics already conducted. 4) To characterize the involvement of genetically polymorphic drug metabolizing enzymes in the human metabolism of the available aromatase inhibitors: letrozole, exemestane and anastrozole in vitro. 5) To test the hypothesis that variants in candidate genes identified in aims 1-4 are associated with well curated phenotypic outcomes, including estrogen metabolite concentrations, pharmacokinetics, hot flashes, breast density, bone metabolism and serum lipid subfractions in breast cancer patients receiving anastrozole, exemestane and letrozole. The results of this proposal will generate new information that, linked with our novel tamoxifen pharmacogenetics findings, will generate a series of genetic tools key to optimizing drug selection for women with breast cancer and to our understanding of the mechanisms of estrogen action.
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