ESTRADIOL METABOLISM - AN ENDOCRINE BIOMARKER FOR MODULATION OF HUMANMAMMARY CARCINOGENESIS

The natural estrogen 17 beta-estradiol (E-2) has a profound influence on proliferation and neoplastic transformation of mammary epithelium. The role of cellular metabolism of E-2 in mammary carcinogenesis, howe ver, remains to be elucidated. Explant culture and cell culture models developed from noncancerous human mammary tissue were used to examine modulation of E-2 metabolism in response to treatment with prototype rodent mammary carcinogens and the ability of the naturally occurring phytochemical indole-3-carbinol (I3C) to influence E-2 metabolism and regulate aberrant proliferation. In the two models, treatment with the chemical carcinogens 7, 12-dimethylbenz[a]anthracene and benzo[a]pyre ne altered the metabolism of E-2 as determined from the radiometric (t ritium release) and gas chromatography-mass spectrometry (GC-MS) assay s. This alteration in E-2 metabolism was accompanied by aberrant proli feration and abrogation of apoptosis as determined by the extent of re plicative DNA synthesis, S-phase fraction and Sub G(0) (apoptotic) pea k. Exposure of carcinogen-initiated cultures to I3C resulted in induct ion of C2-hydroxylation of E-2 and of apoptosis and downregulation of hyperproliferation. Determination of altered cellular metabolism of E- 2 in response to initiators and modulators of carcinogenesis and evalu ation of cell cycle related markers for proliferation and apoptosis ma y provide a mechanism-oriented approach to validate E-2 metabolism as an endocrine biomarker for induction and prevention of human mammary c arcinogenesis.