Mini reviewEstrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis
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.
References (77)
- et al.
The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer
Gynecol. Oncol.
(1995) - et al.
Pathology of epithelial ovarian cancer
Obstet. Gynecol. Clin. North Am.
(1994) The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes?
Gynecol. Oncol.
(1999)Incessant ovulation—a factor in ovarian neoplasia?
Lancet
(1971)- et al.
Hormone replacement therapy and endometrial, ovarian and colorectal cancer
Best Pract. Res. Clin. Endocrinol. Metab.
(2003) - et al.
A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer
J. Clin. Epidemiol.
(2000) - et al.
ER beta: identification and characterization of a novel human estrogen receptor
Fed. Eur. Biochem. Soc. Lett.
(1996) - et al.
Localization of the estrogen receptor locus (ESR) to chromosome 6q25.1 by FISH and a simple post-FISH banding technique
Genomics
(1993) - et al.
Expression of steroid receptors and proteins related to apoptosis in endometria of women with polycystic ovary syndrome
Fertil. Steril.
(2003) - et al.
Characterization of messenger RNA expression of estrogen receptor-alpha and -beta in patients with ovarian endometriosis
Fertil. Steril.
(2000)
Tamoxifen therapy for ovarian cancer in the adjuvant and advanced settings: systematic review of the literature and implications for future research
Gynecol. Oncol.
Absence of estrogen receptor-beta expression in metastatic ovarian cancer
Obstet. Gynecol.
Estrogen and progesterone receptor subtype expression in normal and malignant ovarian epithelial cell cultures
Am. J. Obstet. Gynecol.
Estrogen and progesterone receptors in ovarian epithelial tumors
Mol. Cell. Endocrinol.
Cloning and characterization of human estrogen receptor beta promoter
Biochem. Biophys. Res. Commun.
Steroid receptors in ovarian carcinoma: immunohistochemical determination may lead to new aspects
Gynecol. Oncol.
Steroid hormones and cancer: (III) observations from human subjects
Eur. J. Surg. Oncol.
Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer
Am. J. Pathol.
Estrogen receptor beta expression in invasive breast cancer
Hum. Pathol.
Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis
Fed. Eur. Biochem. Soc. Lett.
Expression of human estrogen receptor using an efficient adenoviral gene delivery system is able to restore hormone-dependent features to estrogen receptor-negative breast carcinoma cells
Mol. Cell. Endocrinol.
Identification of genes involved in growth inhibition of breast cancer cells transduced with estrogen receptor
Fed. Eur. Biochem. Soc. Lett.
Estrogen replacement therapy and fatal ovarian cancer
Am. J. Epidemiol.
Cancers of the breast, endometrium and ovary: geographic correlations
Eur. J. Cancer Clin. Oncol.
Ovarian and endometrial cancers
Cancer Surv.
Hormonal aspects of epithelial ovarian cancer: review of epidemiological evidence
Clin. Endocrinol. (Oxf)
Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone
J. Natl. Cancer Inst.
Initial and cyclic recruitment of ovarian follicles
Endocr. Rev.
Hormonal regulation of the differentiation of cultured ovarian granulosa cells
Endocr. Rev.
Ovarian surface epithelium, ovulation and carcinogenesis
Biol. Rev. Camb. Philos. Soc.
Risk factors and risk reduction of breast and ovarian cancer
Curr. Opin. Obstet. Gynecol.
Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women
J. Natl. Cancer Inst.
An epidemiologic study of epithelial carcinoma of the ovary
Am. J. Epidemiol.
Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II)
J. Am. Med. Assoc.
Menopause and ovarian cancer
Am. J. Epidemiol.
Does HRT modify risk of gynecological cancers?
Int. J. Fertil. Menopausal Stud.
Roles of the ovarian surface epithelium in ovulation and carcinogenesis
Reproduction
Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women
J. Am. Med. Assoc.
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