Estrogens and epithelial ovarian cancer

doi:10.1016/j.ygyno.2004.03.026

Gynecologic Oncology

Volume 94, Issue 1, July 2004, Pages 25-32

https://doi.org/10.1016/j.ygyno.2004.03.026 Get rights and content

Abstract

Objective. Molecular mechanisms involved in ovarian carcinogenesis are still unclear, but there is growing evidence that estrogens promote tumor progression in an epithelial ovarian cancer (EOC) subgroup.

Methods. We reviewed current knowledge on the effects of estrogens in ovarian carcinogenesis and new potential research focuses concerning hormonal therapy of EOC.

Results. Experimentally, estrogen stimulates the growth of ovarian tumor cell lines expressing estrogen receptors (ER). We and other authors have demonstrated differential expression of ERα or β during ovarian carcinogenesis, with overexpression of ERα as compared to ERβ in cancer. This differential expression in ER suggests that estrogen-induced proteins may act as ovarian tumor-promoting agents. Among these proteins, c-myc, fibulin-1, cathepsin-D, or several kallikreins may play a role, since high expression levels have been found in EOC. Consistently, recent prospective epidemiological studies have indicated that estrogen replacement therapy in postmenopausal women may increase ovarian cancer incidence and mortality.

Conclusion. Questions on the estrogen-sensitivity and potential benefits of new hormone therapies in an EOC subgroup should be readdressed in the light of recent experimental and clinical data.

Introduction

Ovarian cancer is the fourth-ranking cause of cancer death in women from western countries [1]. The natural history of this cancer is characterized by a particularly aggressive local invasion potential [2]. Approximately 90% of ovarian cancers arise from ovarian surface epithelial cells (OSE) [3]. The etiological factors involved in ovarian epithelial carcinogenesis have not yet been clearly defined, but recent epidemiological studies have pointed out that estrogen could be responsible for promoting ovarian tumor progression in postmenopausal women. There is also growing experimental evidence that estrogens may play an important role in ovarian carcinogenesis.

Section snippets

Clinical data: estrogen as a promoting factor?

Two clinical questions deserve to be reexamined in light of recent literature: (i) the risk of ovarian cancer under hormonal replacement therapy (HRT), and (ii) the clinical response to antiestrogen therapies.

Role of estrogens, estrogen receptors, and estrogen-induced proteins in ovarian tumor progression

Ovaries are not only the principal source of systemic estrogens in premenopause but also key target tissues of estrogen. Estradiol (E2) and estrone (E1) are mainly produced from follicular thecal cells. Estrogen receptors (ER) α and β are expressed in normal OSE cells as well as in malignant cells [25], [26], [27], [28]. Ovarian epithelial cell proliferation, like in breast cancer cells, may thus be estrogen-dependent through gene regulation (Fig. 3).

Potential clinical application: new markers and targeted therapy prospects

There are two main clinical goals of research driven by progress achieved on molecular ovarian cancer mechanisms: early ovarian cancer detection and targeted therapies.

Conclusion

There is an emerging body of evidence from both clinical and experimental data that EOC growth could actually be estrogen-sensitive. Numerous estrogen-induced proteins have been characterized in ovarian cancer cell lines and might have a role in tumor progression. The involvement of these estrogen-induced proteins in ovarian carcinogenesis, together with the recent epidemiological data on the risk of EOC under estrogen replacement therapy, should lead to reexamination of the sensitivity of an

Acknowledgements

We thank Dr. P. Roger for providing us morphological data and Dr J. Stirnemann for his technical assistance. This work was supported by a grant of the “Centre Hospitalier et Universitaire” of Montpellier (AOI 7619) and the “Ligue Nationale Contre le Cancer.”

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Estrogens and epithelial ovarian cancer

Abstract

Introduction

Section snippets

Clinical data: estrogen as a promoting factor?

Role of estrogens, estrogen receptors, and estrogen-induced proteins in ovarian tumor progression

Potential clinical application: new markers and targeted therapy prospects

Conclusion

Acknowledgements

Obstet. Gynecol.

Gynecol. Oncol.

J. Clin. Epidemiol.

Obstet. Gynecol.

Gynecol. Oncol.

J. Steroid Biochem. Mol. Biol.

FEBS Lett.

FEBS Lett.

Obstet. Gynecol.

Mol. Cell. Endocrinol.

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

Crit. Rev. Oncol./Hematol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

J. Steroid Biochem. Mol. Biol.

Am. J. Pathol.

Eur. J. Cancer

Ann. Oncol.

Gynecol. Oncol.

Cancer statistics, 2000

CA Cancer J. Clin.

Molecular approaches to diagnosis and management of ovarian cancer

Cancer Metastasis Rev.

Ovarian surface epithelium: biology, endocrinology, and pathology

Endocr. Rev.

Noncontraceptive estrogen use and the occurrence of ovarian cancer

J. Natl. Cancer Inst.

Risk factors for ovarian cancer: a case-control study

Br. J. Cancer

Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study. Survey of Women's Health Study Group

Int. J. Cancer

Hormone replacement therapy and risk of epithelial ovarian cancer

Br. J. Cancer

Estrogen replacement therapy and ovarian cancer risk

Int. J. Cancer

Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy

Br. J. Obstet. Gynaecol.

Risk of cancer in women receiving hormone replacement therapy

Int. J. Cancer

Estrogen replacement therapy and fatal ovarian cancer

Am. J. Epidemiol.

Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women

JAMA

Menopausal hormone replacement therapy and risk of ovarian cancer

JAMA

Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women

J. Natl. Cancer Inst.

Hormonal therapy for menopause and ovarian cancer in a collaborative re-analysis of European studies

Int. J. Cancer

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial

JAMA

Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial

JAMA

Endocrine factors in common epithelial ovarian cancer

Endocr. Rev.

Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients

Cancer

Expression of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells

Mol. Hum. Reprod.

Differential expression of estrogen receptor-alpha and-beta messenger RNAs as a potential marker of ovarian carcinogenesis

Cancer Res.

Expression of human estrogen receptor-alpha and-beta, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

Proc. Natl. Acad. Sci. U. S. A.

Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues

J. Clin. Endocrinol. Metab.

Estradiol stimulates cell growth and secretion of procathepsin D and a 120-kilodalton protein in the human ovarian cancer cell line BG-1

J. Clin. Endocrinol. Metab.

Estrogen and anti-estrogen effects on the growth of human epithelial ovarian cancer in vitro

Obstet. Gynecol.