Knockout and expression studies suggest that estrogen receptor ␤ (ER␤) 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 ER␤ levels in 58 ovarian cancer patients, that ER␤ expression decreased in cysts and ovarian carcinomas as compared with normal ovaries and that this decrease is attributable only to a selective loss in

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... R␤ expression during cancer progression. To address the question of a possible involvement of ER␤ in ovarian cancers, we restored ER␣ and ER␤ expression in two human ovarian cancer cell lines PEO14 (ER␣-negative) and BG1 (ER␣-positive) using adenoviral delivery. ER␣, but not ER␤, could induce progesterone receptor and fibulin-1C. Moreover, ER␣ and ER␤ had opposite actions on cyclin D1 gene regulation, because ER␤ down-regulated cyclin D1 gene expression, whereas ER␣ increased cyclin D1 levels. Interestingly, ER␤ expression strongly inhibited PEO14 and BG1 cell proliferation and cell motility in a ligandindependent manner, whereas ER␣ had no marked effect. Induction of apoptosis by ER␤ also contributed to the decreased proliferation of ovarian cancer cells, as shown by Annexin V staining. This study shows that ER␤ is an important regulator of proliferation and motility of ovarian cancer and provides the first evidence for a proapoptotic role of ER␤. The loss of ER␤ expression may thus be an important event leading to the development of ovarian cancer.