Expression Profiles Provide Insights into Early Malignant Potential and Skeletal Abnormalities in Multiple Endocrine Neoplasia Type 2B Syndrome Tumors

Abstract

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