The important role of estrogen(s) (especially estradiol) in the development and progression of breast cancer is well documented, but direct measurement of total plasma, estrone and estradiol does not show significantly higher estrogen levels in breast cancer patients than in controls. Secondly, in postmenopausal women, circulating levels of estradiol are too low to provide potent estrogenic stimulus to breast tissue. Recently, local metabolic transformation of steroids is thought to be of primary importance in providing an estradiol source to human breast tumors. Tissue levels of steroids (estrogen, progestins, androgen) and the factors produced by malignant tumor cells appear to regulate the local interconversion of androgens and estrogens. The proposed study directly addresses the significance of local in situ steroid converting activities 17 beta-hydroxy steroid dehydrogenase (17 beta-OH-SDH) aromatase, sulfatase and sulfotransferase in providing estrogenic stimulus to the malignant tumors. An in- depth understanding of these major pathways of cellular steroid (androgens, estrogens) metabolism and their regulation by other steroids and tumor derived factors will be helpful in providing better specific therapeutic treatment for human breast cancer. Specific objectives of the study are: 1. Identify physiological significance of local metabolic transformation of steroids (androstenedione lead to estrogen leads to estradiol; estrone, estradiol leads to E1SO4) in malignant and nonmalignant breast cells - - a possible estradiol source available to the tumor in postmenopausal women. 2. Determine the regulation of metabolic transformation of estrogens and androgens mediated via 17 beta-OH-SDH, sulfatase, sulfotransferase by estrogens, progestins and androgens and antisteroids in human breast cells. 3. Evaluate whether local interconversion of estrogens (E1 leads to E2) in adipose breast tissue adjacent to tumor mass could provide a major source of estradiol available to tumor mass. 4. Investigate whether enzyme activities in adipose breast tissue adjacent to malignant tumor mass are regulated by the factors secreted from the malignant cells. 5. To study the significance of estradiol in progression and development of breast cancer. 6. Clinically determine the physiological significance of intra/extra- tumoral transformation of steroids in breast cancer so that the potential for local control of estradiol synthesis by specific hormonal or chemotherapeutic agents could be exploited.
