Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

Abstract

The estrogen receptor (ER) has functionality in selected ovarian cancer subtypes and represents a potential target for therapy. The majority (>80%) of high grade serous, low grade serous and endometrioid carcinomas and many granulosa cell tumors express ER-alpha (ERα), and these tumor types have demonstrated responses to endocrine therapy (tamoxifen and aromatase inhibitors) in multiple clinical studies. Biomarkers of responses to these drugs are actively being sought to help identify responsive cancers. Evidence for both pro-proliferative and pro-migratory roles for ERα has been obtained in model systems. ER-beta (ERβ) is generally considered to have a tumor suppressor role in ovarian cancer cells, being associated with the repression of cell growth and invasion. The differential expression of the specific ERβ isoforms may determine functionality within ovarian cancer cells. The more recently identified G protein-coupled receptor (GPER1; GPR30) has been shown to mediate both tumor-suppressive and tumor-promoting action in ovarian cancer cells, suggesting a more complex role. This review will summarize recent findings in this field.

The Cell-Free Expression of MiR200 Family Members Correlates with Estrogen Sensitivity in Human Epithelial Ovarian Cells

“…Both of them are members of the nuclear receptor superfamily and function as transcription factors in response to ligand attachment [ 15 ]. ERα-mediated estrogen signaling was shown to be crucial in the development of ovarian cancer, supported by the observation that ERα is frequently overexpressed in ovarian tumors, and that anti-estrogen treatments such as the application of tamoxifen or aromatase inhibitors improves survival in certain subtypes of ovarian cancer [ 2 , 16 , 17 ]. On the other hand, ERβ is considered to have an antiproliferative effect and shows overexpression in normal tissues [ 16 , 17 , 18 ].…”

Estrogen Receptor Signaling in Cancer

“…Parallel findings for these isoforms and splice variants are also observed in ovarian cancer [ 4 ]. While ERα is associated with the promotion of growth and migration, ERβ has a suppressor role.…”

“…While ERα is associated with the promotion of growth and migration, ERβ has a suppressor role. Again, this inhibitory role of ERβ appears to be mediated by wild-type ERβ1 but can be neutralised by the opposing effects of ERβ2 and ERβ5 [ 4 ]. A role for the nongenomic membrane-bound G-protein coupled receptor (GPER1) is under investigation in this disease and evidence to support both a tumor-promoting and tumor-suppressive role has been obtained.…”

“…A role for the nongenomic membrane-bound G-protein coupled receptor (GPER1) is under investigation in this disease and evidence to support both a tumor-promoting and tumor-suppressive role has been obtained. Both anti-estrogens (tamoxifen and fulvestrant) and aromatase inhibitors (letrozole and anastrazole) have demonstrated antitumor activity in subgroups of ERα-high expressing cancers [ 4 ].…”

PTPRZ1 Inhibits the Cisplatin Resistance of Ovarian Cancer by Regulating PI3K/AKT/mTOR Signal Pathway

“…OC is susceptible to di cult early diagnosis, chemoresistance and recurrence, with 5-year survival rate of only about 40%, thus it has been a hotspot among clinicians (12). Main causes for low survival rate of OC include low early diagnosis and susceptibility to recurrence or metastasis.…”