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Estrogen-induced loss of progesterone receptor expression in normal and malignant ovarian surface epithelial cells

Oncogene volume 24, pages 4388–4400 (2005)Cite this article

Abstract

While estrogens are suspected risk factors for epithelial ovarian cancer (OCa), progesterone (P4) has been shown to exert protective effects. The biological actions of P4 in target cells are mediated by progesterone receptors (PRs) that exist principally as A- and B-isoforms. We observed overexpression of PR-A and PR-B protein in two lines of OCa cells when compared to two lines of nontumorigenic, normal human ovarian surface epithelial (HOSE) cells. Treatment of HOSE or OCa cells with estrone or 17β-estradiol at 10−8 M for a period of 72 h induced significant loss of PR-A and PR-B mRNA and protein expression, with the regulation primarily controlled at the transcriptional level. In contrast, breast cancer cells (line MCF-7) exposed to estrogens upregulated PR-A and PR-B expression. Of significance, both the inhibitory and stimulatory actions of estrogens were blocked by the specific ER-antagonist ICI 182,780 (ICI, 10−5 M), confirming estrogen specificity. Cotreatment of estrogen-exposed HOSE, OCa and MCF-7 cell lines with inhibitors of type 1- and type 2-17β hydroxysteroid dehydrogenase did not affect the previously observed changes in PR expression, suggesting that the action of each estrogen is direct and not mediated via conversion to its metabolic counterpart. Green fluorescence protein (GFP)-PR-A and GFP-PR-B were localized in the cytoplasmic compartment of untreated HOSE cells and translocated to the nucleus after P4 treatment, while both chimera PRs resided in the nuclei of OCa cells in a ligand-independent manner. In OCa cell cultures, P4 (10−6 M), but not RU486 (10−5 M), induced apoptosis that was blocked by cotreatment with the antiprogestin but enhanced by cotreatment with ICI. In sharp contrast, P4 induced proliferation, while ICI and RU486 caused cell death in MCF-7 cells. In conclusion, this study is first to demonstrate estrogens as negative regulators of PR expression in HOSE/OCa cells and to provide a mechanistic basis upon which to explain the antagonism of estrogens on the anti-OCa action of progestins. It also raises the possibility of using progestin and ICI as a combinational therapy for OCa treatment.

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Acknowledgements

We thank the editorial staff of Brigham and Women's Hospital, Harvard Medical School, Boston, for editorial help. This study was supported in part by NIH Grants CA091250 (to V Syed) and CA94221 and DK61084 (to S-M Ho).

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  1. Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA

    Kasturi Mukherjee, Viqar Syed & Shuk-Mei Ho

  2. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA

    Shuk-Mei Ho

  3. Department of Physiology, University of Massachusetts Medical School, Worcester, MA, USA

    Shuk-Mei Ho

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Mukherjee, K., Syed, V. & Ho, SM. Estrogen-induced loss of progesterone receptor expression in normal and malignant ovarian surface epithelial cells. Oncogene 24, 4388–4400 (2005). https://doi.org/10.1038/sj.onc.1208623

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