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Involvement of Estrogen Receptor ß in Ovarian Carcinogenesis

¹ Unité INSERM 540, Montpellier, France; ² Laboratoire de Biologie Cellulaire et Hormonale, Hôpital Arnaud de Villeneuve, Montpellier, France; and the ³ Department of Obstetrics and Gynecology, University of Turin, Turin, Italy

Knockout and expression studies suggest that estrogen receptor ß (ERß) plays a prominent role in ovarian function and pathology. Moreover, ovarian cancers are characterized by high morbidity and low responsiveness to anti-estrogens. Here we demonstrate, using quantitative PCR to measure ER and ERß levels in 58 ovarian cancer patients, that ERß expression decreased in cysts and ovarian carcinomas as compared with normal ovaries and that this decrease is attributable only to a selective loss in ERß expression during cancer progression. To address the question of a possible involvement of ERß in ovarian cancers, we restored ER and ERß expression in two human ovarian cancer cell lines PEO14 (ER-negative) and BG1 (ER-positive) using adenoviral delivery. ER, but not ERß, could induce progesterone receptor and fibulin-1C. Moreover, ER and ERß had opposite actions on cyclin D1 gene regulation, because ERß down-regulated cyclin D1 gene expression, whereas ER increased cyclin D1 levels. Interestingly, ERß expression strongly inhibited PEO14 and BG1 cell proliferation and cell motility in a ligand-independent manner, whereas ER had no marked effect. Induction of apoptosis by ERß also contributed to the decreased proliferation of ovarian cancer cells, as shown by Annexin V staining. This study shows that ERß is an important regulator of proliferation and motility of ovarian cancer and provides the first evidence for a proapoptotic role of ERß. The loss of ERß expression may thus be an important event leading to the development of ovarian cancer.

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