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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA046423-01
Application #
3458598
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1988-03-01
Budget End
1989-02-28
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Mehta, R R; Graves, J M; Hart, G D et al. (1993) Growth and metastasis of human breast carcinomas with Matrigel in athymic mice. Breast Cancer Res Treat 25:65-71
Mehta, R R; Das Gupta, T K (1993) Regulation of 17 beta-hydroxysteroid dehydrogenase in a newly-established human breast carcinoma cell line. J Steroid Biochem Mol Biol 46:623-9
Mehta, R R; Graves, J M (1992) Breast tumor-derived factors stimulate reduction of estrone to estradiol in nonmalignant breast tissue. Breast Cancer Res Treat 23:51-6
Mehta, R R; Beattie, C W; Das Gupta, T K (1992) Endocrine profile in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat 20:125-32
Mehta, R R; Hart, G; Das Gupta, T K (1992) Steroid receptors in breast cancer patients. Influence of obesity and age at diagnosis. Anticancer Res 12:1311-4
Mehta, R R; Bratescu, L; Graves, J M et al. (1992) Human breast carcinoma cell lines: ultrastructural, genotypic, and immunocytochemical characterization. Anticancer Res 12:683-92
Mehta, R R; Hart, G D (1990) Cellular retinol binding protein and breast carcinoma. Eur J Cancer 26:888-91