Estrogen is a risk factor for breast cancer. Genetic variation is responsible for functional differences in biosynthetic enzymes and transcription factors. Estrogen is synthesized by a succession of enzymatic reactions and it exerts its cellular responses through a nuclear receptor. Polymorphic enzymes, or modified receptor, could lead to differences in the physiological levels of estrogen within individuals and between ethnic groups. Such variation in estrogen levels could contribute to altered breast cancer risk. We propose to examine two proteins involved in the regulation of steroid biosynthesis, Steroidogenic Acute Regulatory protein (StAR) and Steroidogenic Factor- 1/Adrenal4 Binding Protein (SF-1/Ad4BP), for the presence of genetic diversity. StAR facilities transport of cholesterol across the mitochondrial membrane to cytochrome P450scc which converts cholesterol to the steroid precursor, pregnenolone. SF-1/Ad4BP regulates cell-type specific and hormonal expression of many steroidogenic enzymes, including the cytochrome p450 steroid hydroxylases and StAR. We will associate significant polymorphisms with breast cancer risk in a pilot, case-control study of Caucasians (a high risk group) and Asians (a lower risk population). Concurrently, polymorphisms within likely functional regions will be examined by specific in vitro molecular assays to ascertain their effect on estrogen biosynthesis.
