Involvement of Estrogen Receptor β in Ovarian Carcinogenesis

Abstract

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 ER␤ 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.

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

“…These initial findings had not taken into account the presence of ER subtypes. Both ERa and ERb were found to be present in both normal ovarian tissues and ovarian cancer tissues, with a possible reduction of ERb expression as tumors progress (Bardin et al 2004a, Chan et al 2008. The loss of ERb expression indicates that ERb exerts tumor-suppressive functions and may have a protective role.…”

O papel do 17β-estradiol no processo luteolítico de cadelas não prenhes

“…A similar downregulation of ERβ has also been noted in prostate, breast, and colon tumors (CAMPBELL-THOMPSON;LYNCH;BHARDWAJ, 2001;ROGER et al, 2001;CHENG et al, 2004). It has been reported that ERβ up-regulates apoptosis in ovarian cancer cells (BARDIN et al, 2004b) and enhances FasL expression, a major extrinsic apoptotic regulator, in normal ovarian cells (SAPI et al, 2002 CHENG et al, 2004) cancer cells. Thus, similar to the cow, luteolysis in the dog is multifactorial and can occur via both apoptotic pathways .…”

Steroid hormone receptor signaling in tumorigenesis

“…Accordingly, the ratio of ERa to ERb was observed to increase during carcinogenesis [Pujol et al, 1998;Rutherford et al, 2000], strengthening the concept of ERa as promoting tumorigenesis while ERb of preventing it. As additional proof is loss of the ERb expression could be one of the leading events to breast and ovarian carcinogenesis [Lazennec et al, 2001;Bardin et al, 2004]. Mechanistic studies of the functions of ERb are revealing the reason behind its anti-proliferative effects in contrast to ERa.…”