Cancer Letters

Cancer Letters

Volume 231, Issue 2, 18 January 2006, Pages 151-157
Cancer Letters

Mini review
Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

https://doi.org/10.1016/j.canlet.2005.01.021Get rights and content

Abstract

Ovarian cancer is one of the leading causes of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed.

Section snippets

Ovarian cancer pathology

Ovarian cancer (OCa) is the leading cause of death from gynecological tumors and is the fourth most frequent cause of death from cancer in women [1]. The incidence of OCa varies widely in frequency among different geographic regions and ethnic groups, with high incidences observed in Scandinavia, Western Europe and North America and low incidences found in Asian countries [2]. The incidence of OCa also increases with age as it is relatively rare in women younger than 30 years [3]. The majority

Estrogens and ovarian cancer

The ovary is the main source of estrogen in women, the estrogen being formed in granulosa cells from androgenic precursors derived from the theca. In the ovary, oocytes in primordial follicles can remain dormant for years until stimulated to develop. A complex network of endocrine and paracrine signals is involved in the recruitment of dormant oocytes into the growth pool [10]. Estrogen critically affects the growth and development of ovarian follicles during the female reproductive cycle

Lessons from ERα and ERβ knock out mice

Although, mouse physiology is clearly different from human, knock out experiments targeting ERα or ERβ genes have been useful for the understanding of the role of both receptors in ovary physiology. ERα knockout (ERKO) females are infertile and develop multiple hemorrhagic ovarian cysts [31], [32]. ERβ knockout mice (BERKO) display more subtle reproductive deficits, including female subfertility owing to accelerated follicular atresia and decreased responsiveness to the gonadotropins [33]. At 2

Distribution of ERβ in normal ovary

Several studies have indicated that ERα mRNA is predominant in the uterus, mammary gland, testis, pituitary, liver, kidney, heart, and skeletal muscle, whereas ERβ transcripts are significantly expressed in the ovary and prostate [35], [36], [37]. In humans, ERβ RNA and protein have has been found in epithelial and stromal cells [38], [39]. ERα and ERβ have been also observed in freshly isolated primary OSE and granulosa (GC) cell cultures [40], [41]. The presence of easily detectable levels of

ERβ expression in tumors

Contrasting with breast cancer, the prognostic value of hormonal receptor status has not been clearly established for OCa [42], [43]. Widespread expression of ERα is observed in all tumor types, but at relatively low levels. ERβ is expressed predominantly in GCT tumors [44]. Until recently, little was known about expression levels of the estrogen receptors (ERs) in ovarian epithelial tumors or in normal OSE. The early work from our laboratory and others has shown that in ovarian cancer samples,

ERβ, anti-estrogen resistance

Therapy with the antiestrogen, tamoxifen, is an effective treatment of about 50% of ER-positive breast cancers, whereas only 15–18% of ER-positive OCa initially respond to antiestrogen therapy [58], [59]. Two forms of antiestrogen resistance occur (i) de novo resistance and (ii) acquired resistance. Absence of estrogen receptors is the most common mechanism of de novo resistance. In the case of acquired resistance, a complete loss of estrogen receptor expression is not, however, a common

ERβ targeted therapy

With these data, we are faced to the striking result that ERβ expression is lost when ovary, breast or prostate turn cancerous. About 6 years ago, we hypothesized that this decreased expression could reflect tumor suppressor properties for ERβ. This idea was further reinforced by the fact that ERβ is localized on 14q chromosome, a region which displays frequent partial deletions in OCa [69]. To test this hypothesis, we decided to restore ERβ expression in cancer cells expressing low levels of

Conclusion

In summary, the decreased expression of ERβ observed in ovarian cancers opens the debate whether ERβ could be a tumor-suppressor. Results obtained from cellular or animal models in which ERβ was exogenously expressed, show that this receptor is definitely an interesting target for cancer therapy. As ovarian cancer is the first cancer in women in terms of morbidity and since this cancer display a rapid and dramatic development, strategies able to restore or to increase ERβ expression or activity

Acknowledgements

This work was supported by grants from ARC (Association pour la Recherche contre le Cancer, Grant No. 3582) and from the the Ligue Nationale contre le Cancer.

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