Nitin T. Telang, Meena Katdare, H. Leon Bradlow, and Michael P. Osborne
Strang Cancer Research Laboratory, The Rockefeller University, New York, New York
The natural estrogen 17ß-estradiol (E2) has a profound influence on proliferation and neoplastic transformation of mammary epithelium. The role of cellular metabolism of E2 in mammary carcinogenesis, however, remains to be elucidated. Explant culture and cell culture models developed from noncancerous human mammary tissue were used to examine modulation of E2 metabolism in response to treatment with prototype rodent mammary carcinogens and the ability of the naturally occurring phytochemical indole-3-carbinol (I3C) to influence E2 metabolism and regulate aberrant proliferation. In the two models, treatment with the chemical carcinogens 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene altered the metabolism of E2 as determined from the radiometric (tritium release) and gas chromatography-mass spectrometry (GC-MS) assays. This alteration in E2 metabolism was accompanied by aberrant proliferation and abrogation of apoptosis as determined by the extent of replicative DNA synthesis, S-phase fraction and Sub G0 (apoptotic) peak. Exposure of carcinogen-initiated cultures to I3C resulted in induction of C2-hydroxylation of E2 and of apoptosis and downregulation of hyperproliferation. Determination of altered cellular metabolism of E2 in response to initiators and modulators of carcinogenesis and evaluation of cell cycle related markers for proliferation and apoptosis may provide a mechanism-oriented approach to validate E2 metabolism as an endocrine biomarker for induction and prevention of human mammary carcinogenesis. -- Environ Health Perspect 105(Suppl 3):559-564 (1997)
Key words: estrogen metabolites, mammary carcinogenesis, chemoprevention, in vitro models
This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 15 August 1996.
Supported in part by Department of Defense grant DAMD-17-94-J-4208, National Institute of Health grant P01 CA 29502, Indo-US Fulbright fellowship#17267, and philanthropic funds to the Strang Cancer Prevention Center.
The authors acknowledge the expert technical assistance of M. Zvanovec and skillful editorial assistance of K.J. Brady.
Address correspondence to Dr. N.T. Telang, Division of Carcinogenesis and Prevention, Strang Cancer Research Laboratory, The Rockefeller University, Box 231, 1230 York Avenue, New York, NY 10021. Telephone: (212) 734-0567, ext. 213. Fax: (212) 472-9471.
Abbreviations used: AP, apoptosis; B[a]P , benzo[a]pyrene; BSTFA, bis(trimethylsilyl)trifluroacetamide; cyp450, cytochrome P450; DMBA, 7,12-dimethylbenz[a]anthracene; DMSO, dimethyl sulfoxide; E2, 17-ß estradiol; FACS, fluorescene assisted cell sorting; G0, resting phase; G1, first growth phase; G2, second growth phase; GC-MS, gas chromatography-mass spectrometry; I3C, indole-3-carbinol; M, mitosis; NS, not significant; S, synthesis phase; 2-OHE1, 2-hydroxyestrone; 16
-OHE, 16-hydroxyestrone; TDLU, terminal duct lobular units.
Last Update: April 10, 1997