Summary
Ovarian cancer is the leading cause of gynecological cancer mortality, and 85–90% of this malignancy originates from the ovarian surface epithelium (OSE). The etiology of ovarian epithelial cancer is unknown but a role for estrogens has been suspected. However, the effect of estrogens on OSE cell proliferation remains to be determined. Using the rabbit model, our studies have demonstrated that 17β-estradiol stimulates OSE cell proliferation and the formation of a papillary ovarian surface morphology similar to that seen in human ovarian serous neoplasms of low malignant potential. Immunohistochemical staining of ovarian tissue sections with an antibody to the estrogen receptor α demonstrates its expression in both OSE cells and stromal interstitial cells. In primary ovarian cell cultures, the proliferative response of the epithelial cells to 17β-estradiol depends on the expression of the estrogen receptor α in the epithelial cells. However, when the epithelial cells are grown together with ovarian stromal cells, their proliferative response to this hormone is greatly enhanced, suggesting the involvement of stromal-epithelial interactions. These studies suggest a role for estrogens and the estrogen receptor α in OSE growth.
Similar content being viewed by others
References
Abu-Jawdeh, G. M.; Jacobs, T. W.; Niloff, J.; Canistra, S. A. Estrogen receptor expression is a common feature of ovarian borderline tumors. Obstet. Gynecol. 60:301–307; 1996.
Adams, A. T.; Auersperg, N. Autoradiographic investigation of estrogen binding in cultured rat ovarian surface epithelial cells. J. Histochem. Cytochem. 31:1321–1325; 1983.
Berthois, Y.; Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc. Natl. Acad. Sci USA 83:2496–2500; 1986.
Bodker, A.; Andersson, K.-E.; Batra, S.; Juhl, B. R.; Meyhoff, H.-H. The distribution of estrogen receptors in the urinary tract of the male rabbit: an immunological and biochemical study. Scand. J. Urol. Nephrol. 27:169–174; 1993.
Bradenberger, A. W.; Tee, M. K.; Jaffe, R. B. Estrogen receptor alpha (ER-α) and beta (ER-β) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-β in neoplastic tissues. J. Clin. Endocrinol. Metab. 83:1025–1028; 1998.
Buchanan, D. L.; Kurita, T.; Taylor, J. A.; Lubahn, D. B.; Cunha, G. R.; Cooke, P. S. Role of stromal and epithelial estrogen receptors in vaginal epithelial proliferation, stratification, and cornification. Endocrinology 139:4345–4352; 1998.
Chambon, M.; Cavalie-Barthez, G.; Veith, F.; Vignon, F.; Hallowes, R.; Rochefort, H. Effect of estradiol on nonmalignant human mammary cells in primary culture. Cancer Res. 44:5733–5743; 1984.
Cooke, P. S.; Buchanan, D. L.; Young, P., et al. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc. Natl. Acad. Sci. USA 94:6535–6540; 1997.
Cunha, G. R. Growth factors as mediators of androgen action during male urogenital development. 6 (Suppl. Prostate):22–25; 1996.
Evans, R. M. The steroid and thyroid hormone receptor superfamily. Science 240:889–895; 1988.
Galtier-Dereure, F.; Capony, F.; Mauedelonde, T.; Rochefort, H. Estradiol stimulate cell growth and secretion of procathepsin D and a 120-kilodalton protein in the human ovarian cancer cell line BG-1. J. Clin. Endorinol. Metab. 75:1497–1502; 1992.
Geisinger, K. R.; Berens, M. E.; Duckett, Y.; Morgan, T. M.; Kute, E.; Welander, C. E. The effects of estrogen, progesterone and tamoxifen alone and in combination with cytoxic agents against human ovarian carcinoma in vitro. Cancer 65:1055–1061; 1990.
Ghossain, M. A.; Buy, J.-N.; Lignères, C., et al. Epithelial tumors of the ovary: comparison of MR and CT findings. Radiol. 181:863–870; 1991.
Giacomini, C.; Nicosia, S. V.; Sauders, B. O.; Fultz, C.; Sun, X.; Jasonni, V. M. Ovarian mesothelial and extramesothelial cells in interactive culture. In Vitro Cell. Dev. Biol. 31:300–309; 1995.
Granberg, S.; Wikland, M.; Jansson, I. Macroscopic characterization of ovarian tumors and the relation to the histological diagnosis: criteria to be used for ultrasound evaluation. Obstet. Gynecol. 35:139–144; 1989.
Hamilton, T. C.; Davies, P.; Griffiths, K. Androgen and oestrogen binding of cytosols of human ovarian tumors. J. Endocrinol. 90:421–431; 1981.
Humphreys, R. C.; Lydon, J.; O'Malley, B. W.; Rosen, J. M. Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol. Endocrinol. 11:801–811; 1997.
Ignar-Trowbridge, D. M.; Nelson, K. G.; Bidwell, M. C.; Curtis, S. W.; Washburn, T. F.; Machlachlan, J. A.; Korach, K. S. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc. Natl. Acad. Sci. USA 89:4658–4662; 1992.
Isola, J.; Kallioniemi, O.-P.; Korte, J.-M.; Wahlstrom, T.; Aine, R.; Helle, M.; Helin, H. Steroid receptors and Ki-67 reactivity in ovarian cancer and in normal ovary: correlation with DNA flow cytometry, biochemical receptor assay, and patient survival. J Pathol. 162:295–301; 1990.
Jabara, A. G. Canine ovarian tumors following stilboestrol administration. Aust. J. Exp. Biol. 37:549–566; 1959.
Kommonss, F. Common epithelial ovarian cancer: endocrine factors, hormonal therapy, and new aspects concerning the expression of sex steroid receptors. In: Rasqualini, J. R.; Katzenellenbogen, B. K., ed. Hormone-dependent cancer. New York: Marcel Dekker, 1996:541–572.
Kuiper, G. G. J. M.; Enmark, E.; Peito-Huikko, M.; Nilson, S.; Gustafsson, J.-A. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA 93:5925–5930; 1996.
Langdon, S. P.; Hawkes, M. M.; Lawrie, S. S.; Hawkins, R. A.; Tesdale, A. L.; Crew, A. J.; Miller, W. R.; Smyth, J. F. Oestrogen receptor expression and the effects of oestrogen and tamoxifen on the growth of human ovarian carcinoma cell lines. Br. J. Cancer 62:213–216; 1990.
Langdon, S. P.; Lawrie, S. S.; Hay, F. G., et al. Characterization and properties of nine human ovarian adenocarcinoma cell lines. Cancer Res. 48:6166–6172; 1988.
Lau, K. M.; Mok, S. C.; Ho, S. M. Expression of human estrogen receptor-α and −β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc. Natl. Acad. Sci. USA 96:5722–5727; 1999.
Lee, H.; Jiang, F.; Wang, Q.; Nicosia, S. V.; Yang, J.; Su, B.; Bai, W. MEKK1 activation of human estrogen receptor α and stimulation of the agonistic activity of 4-hydroxytamoxifen in endometrial and ovarian cancer cells. Mol. Endocrinology 14:1882–1896; 2000.
Malet, C.; Conpel, A.; Spritzer, P.; Bricout, N.; Yaneva, H.; Mowszowicz, I.; Kuttenn, F.; Mauvais-Jarvis, P. Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Res. 48:7193–7199; 1988.
Motta, P. M.; Van Blerkom, J.; Makabe, S. Changes in the surface morphology of ovarian germinal epithelium during its reproductive cycle and in some pathological conditions. A correlative three-dimensional analysis by transition, scanning and high voltage electron microscope. J. Submicrosc. Cytol. 12:407–425; 1980.
Nash, J. D.; Ozols, R. F.; Smyth, J. F.; Hamilton, T. C. Estrogen and antiestrogen effects on the growth of human epithelial ovarian cancer cells in vitro. Obstet. Gynecol. 73:1009–1015; 1989.
Nelson, K. G.; Takahashi, T.; Bossert, N. L.; Walmer, D. K.; McLachlan, J. A. Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc. Natl. Acad. Sci. USA 88:21–25; 1991.
Nicosia, S. V. Morphological changes of the human ovary throughout life. In: Serra, G. B., ed. The ovary. New York. Raven Press; 1983:57–81.
Nicosia, S. V.; Nicosia, R. F. Neoplasm of the ovarian mesothelium. In: Azar, H. A., ed. Pathology of human neoplasms. New York: Raven Press; 1988:435–486.
Paech, K.; Webb, P.; Kuiper, G. G. J. M.; Nilsson, S.; Gustafsson, J.-A.; Kushner, P. J.; Scanlan, T. S. Differential ligand activation of estrogen receptors ERα and ERβ at API sites. Science 277:1508–1510; 1997.
Pierro, E.; Nicosia, S. V.; Saunders, B.; Fultz, C. B.; Nicosia, R. F.; Mancuso, S. Influence of growth factors on proliferation and morphogenesis of rabbit ovarian mesothelial cells in vitro. Biol. Reprod. 54:660–669; 1990.
Pujol, P.; Rey, J. M.; Nirde, P.; Roger, P.; Gastaldi, M.; Laffargue, F.; Rochefort, H.; Maudelonde, T. Differential expression of estrogen receptor-alpha and −beta messenger RNAs as a potential marker of ovarian carcinogenesis. Cancer Res. 58:5367–5373; 1998.
Russell, P. Surface epithelial-stroma tumors of the ovary. In: Kurman, R. J., ed. Blaistein's pathology of the femele genital tract, New York, Springer, 1994:705–782.
Saunders, P. T.; Maguire, S. M.; Gaughan, J.; Millar, M. R. Expression of oestrogen receptor beta (ER beta) in multiple rat tissues visualized by immunohistochemistry. J. Endocrinol. 154:R13-R16; 1997.
Scully, R. E. Tumors of the ovary and maldeveloped gonads. In: Hartmann, W. H., ed. Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology. Vol. 2; 1979:58.
Smith, C. L.; Nawaz, Z.; O'Malley, B. W. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol. Endocrinol. 11:657–666; 1997.
Tora, L.; White, J.; Brou, C.; Tasset, D.; Webster, N.; Scheer, E.; Chambon, P. The human estrogen receptor has two independent nonacidic transcriptional activation domains. Cell 59:477–487; 1989.
Tsai, M.-J.; O'Malley, B.W. Molecular mechanisms of action of steroid/thydroid receptor superfamily members. Annu. Rev. Biochem. 63:451–486; 1994.
Tzukerman, M. T.; Esty, A.; Santiso-Mere, D.; Danielian, P.; Parker, M. G.; Stein, R. B.; Pike, W. J.; McDonnell, D. P. Human estrogen receptor transactivation capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol. Endocrinol. 8:21–30; 1994.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bai, W., Oliveros-Saunders, B., Wang, Q. et al. Estrogen stimulation of ovarian surface epithelial cell proliferation. In Vitro Cell.Dev.Biol.-Animal 36, 657–666 (2000). https://doi.org/10.1290/1071-2690(2000)036<0657:ESOOSE>2.0.CO;2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1290/1071-2690(2000)036<0657:ESOOSE>2.0.CO;2