Abstract
Epidemiological studies have implicated androgens in the etiology/progression of epithelial ovarian cancer. Because normal and malignant ovarian epithelial cells are growth inhibited by transforming growth factor (TGF) beta, we tested the ability of 5alpha-dihydrotestosterone (DHT) to modulate this response and the expression of TGF-beta receptor types I and II. Cells derived from the ovarian surface epithelium of women undergoing oophorectomy (n = 7) for nonovarian indications or with a germ-line BRCA1 or 2 mutation (n = 9), and from the ascitic fluid of patients with primary ovarian cancer (n = 8) were cultured with and without DHT. Cell proliferation after TGF-beta1 or vehicle treatment was determined, and transcripts for TGF-beta receptors were measured by quantitative reverse transcription-PCR. As low levels of androgen receptor were observed in the cultures, we also measured transcript levels for steroid receptor coactivators SRC-1, ARA70, and AIB1. TGF-beta1 inhibited growth in 12 of 13 cultures tested, and DHT generally reversed this effect, demonstrating that androgens can block TGF-beta-induced growth inhibition in both malignant and nonmalignant ovarian epithelial cells. Transcripts for TGF-beta receptors, SRC-1, and ARA70 were found to be coordinately regulated by androgen in control cells, but not in either malignant or BRCA1/2-positive cell cultures. These findings raise the possibility that by modulating steroid receptor coactivator expression, androgen might affect other hormonal responses and contribute to the initiation of ovarian cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors
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Activin Receptors, Type I / biosynthesis
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Activin Receptors, Type I / physiology
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Androgens / physiology*
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Cell Division / drug effects
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Cell Division / physiology
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Dihydrotestosterone / pharmacology*
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Female
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Genes, BRCA1*
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Genes, BRCA2*
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Germ-Line Mutation*
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Histone Acetyltransferases
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Humans
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Middle Aged
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Nuclear Receptor Coactivator 1
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Nuclear Receptor Coactivator 3
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Nuclear Receptor Coactivators
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Oncogene Proteins*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology*
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Ovary / cytology*
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Ovary / drug effects
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Ovary / metabolism
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Protein Serine-Threonine Kinases
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Receptors, Transforming Growth Factor beta / biosynthesis
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Receptors, Transforming Growth Factor beta / physiology
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
Substances
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Androgens
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NCOA4 protein, human
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Nuclear Receptor Coactivators
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Oncogene Proteins
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RNA, Messenger
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Receptors, Transforming Growth Factor beta
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Trans-Activators
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Transcription Factors
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Dihydrotestosterone
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Histone Acetyltransferases
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NCOA1 protein, human
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Nuclear Receptor Coactivator 1
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Nuclear Receptor Coactivator 3
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II