The role of estrogen receptor subtypes in ovarian hormonal therapy

Abstract

Estrogen, a steroid hormone mainly synthesized in the ovary, regulates the expression of genes that are responsible for cell proliferation, apoptosis, tumor metastasis and invasion. The effects of estrogen are mediated through estrogen receptors (ER). Previous investigations demonstrated that two major subtypes of ER (α and β) had opposing effects on cell proliferation: ERα promoted cell proliferation, whereas ERβ induced cell apoptosis. Although ovarian cells bear hormone receptors and are hormone sensitive, hormonal therapy in ovarian cancer is not well established. The relationship between cellular responses to hormonal therapy and the expressions of estrogen receptor subtypes is still unclear.

The aim of this study was to investigate the cellular responses of ovarian cancer to selective estrogen receptor modulators in relation to estrogen receptor subtypes expressions. In this study, the effects of a spectrum of estrogen receptor agonist, partial agonist and a newly discovered pure antagonist on the growth of ovarian cancer cells bearing different estrogen receptor subtypes were studied. Using Real-time PCR, we found that 41.6% of ovarian cancer cell lines (5 of 12) showed higher ERα than ERβ mRNA levels (ERα/ERβ ratio>1) whereas all seven normal ovarian cell lines showed higher ERβ levels. Four ovarian cancer cell lines with different expression profiles (ERα+/ERβ+, ERα-/ERβ-, ERα-/ERβ+, ERα+/ERβ-) were selected. Apoptosis and clonogenic assays were used to detect the effects of drugs on cell apoptosis and proliferation respectively. Estradiol (agonist) significantly reduced apoptosis and increased survival of α+/β+ and α+/β- cells, but it had no effect on α-/β- or α-/β+ cells, implying that Estradiol promoted the growth of ovarian cancer cells bearing the ERα receptor subtype. Fulvestrant (pure antagonist) increased apoptosis and reduced survival in all four different cell lines, suggesting that its effects were mediated via a receptor-independent pathway. Tamoxifen (partial agonist) induced apoptosis of α+/β- and α-/β+ cells at different concentrations, but had no effect on α+/β+ and α-/β-cells, suggesting Tamoxifen might have a partial agonist effect on ERα positive cells but a pure antagonist effect on ERβ positive cells. These findings provided some insights into the use of hormonal therapy in ovarian cancer patients with different estrogen receptor subtypes expression profiles.