High-dose estrogen and clinical selective estrogen receptor modulators induce growth arrest, p21, and p53 in primate ovarian surface epithelial cells

Jay W. Wright, Richard Stouffer, Karin D. Rodland

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    Ovarian cancer is the most lethal gynecological cancer affecting women. Hormone-based therapies are variably successful in treating ovarian cancer, but the reasoning behind these therapies is paradoxical. Clinical reagents such as tamoxifen are considered to inhibit or reverse tumor growth by competitive inhibition of the estrogen receptor (ER); however, high-dose estrogen is as clinically effective as tamoxifen, and it is unlikely that estrogen is acting by blocking ER activity; however, it may be activating a unique function of the ER that is nonmitogenic. For poorly defined reasons, 90% of ovarian cancers derive from the ovarian surface epithelium (OSE). In vivo the ER-positive OSE is exposed to high estrogen levels, reaching micromolar concentrations in dominant ovarian follicles. Using cultured rhesus OSE cells in vitro, we show that these levels of estradiol (1 μg/ml; ∼3 μM) block the actions of serum growth factors, activate the G1 phase retinoblastoma checkpoint, and induce p21, an inhibitor of kinases that normally inactivate the retinoblastoma checkpoint. We also show that estradiol increases p53 levels, which may contribute to p21 induction. Supporting the hypothesis that clinical selective ER modulators activate this novel ER function, we find that micromolar doses of tamoxifen and the "pure antiestrogen" ICI 182,780 elicit the same effects as estradiol. We propose that, in the context of proliferation, these data clarify some paradoxical aspects of hormone-based therapy and suggest that a fuller understanding of normal ER function is necessary to improve therapeutic strategies that target the ER.

    Original languageEnglish (US)
    Pages (from-to)3688-3695
    Number of pages8
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume90
    Issue number6
    DOIs
    StatePublished - Jun 2005

    Fingerprint

    Selective Estrogen Receptor Modulators
    Estrogen Receptors
    Primates
    Estrogens
    Epithelial Cells
    Growth
    Tamoxifen
    Ovarian Neoplasms
    Estradiol
    Epithelium
    Retinoblastoma
    Hormones
    G1 Phase Cell Cycle Checkpoints
    Estrogen Receptor Modulators
    Ovarian Follicle
    Therapeutics
    Tumors
    Neoplasms
    Intercellular Signaling Peptides and Proteins
    Phosphotransferases

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology, Diabetes and Metabolism

    Cite this

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    abstract = "Ovarian cancer is the most lethal gynecological cancer affecting women. Hormone-based therapies are variably successful in treating ovarian cancer, but the reasoning behind these therapies is paradoxical. Clinical reagents such as tamoxifen are considered to inhibit or reverse tumor growth by competitive inhibition of the estrogen receptor (ER); however, high-dose estrogen is as clinically effective as tamoxifen, and it is unlikely that estrogen is acting by blocking ER activity; however, it may be activating a unique function of the ER that is nonmitogenic. For poorly defined reasons, 90{\%} of ovarian cancers derive from the ovarian surface epithelium (OSE). In vivo the ER-positive OSE is exposed to high estrogen levels, reaching micromolar concentrations in dominant ovarian follicles. Using cultured rhesus OSE cells in vitro, we show that these levels of estradiol (1 μg/ml; ∼3 μM) block the actions of serum growth factors, activate the G1 phase retinoblastoma checkpoint, and induce p21, an inhibitor of kinases that normally inactivate the retinoblastoma checkpoint. We also show that estradiol increases p53 levels, which may contribute to p21 induction. Supporting the hypothesis that clinical selective ER modulators activate this novel ER function, we find that micromolar doses of tamoxifen and the {"}pure antiestrogen{"} ICI 182,780 elicit the same effects as estradiol. We propose that, in the context of proliferation, these data clarify some paradoxical aspects of hormone-based therapy and suggest that a fuller understanding of normal ER function is necessary to improve therapeutic strategies that target the ER.",
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