Estradiol metabolism: an endocrine biomarker for modulation of human mammary carcinogenesis.
The natural estrogen 17beta-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 (13C) 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 13C 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.
Telang
N T
NT
Strang Cancer Research Laboratory, The Rockefeller University, New York, New York 10021, USA.
Katdare
M
M
Bradlow
H L
HL
Osborne
M P
MP
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000633:toxicity; D015415:Biomarkers; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D046508:Culture Techniques; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D002273:Carcinogens; D004965:Estrogen Antagonists; D007211:Indoles; D001564:Benzo(a)pyrene; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; C016517:indole-3-carbinol; D004121:Dimethyl Sulfoxide