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.

Keywords: GPER; estrogen; estrogen receptor; letrozole; ovarian cancer; tamoxifen.

Figure 1

Estrogen receptor isoforms and mutants found within ovarian cancers. (A) Estrogen receptor alpha isoforms identified in ovarian cancers. (B) Mutated versions of estrogen receptor alpha found in ovarian cancers. Mutations at positions 537 and 538 have been observed. (C) Estrogen receptor beta isoforms identified in ovarian cancers. AF1 = Activation function 1; DBD = DNA binding domain; AF2 = Activation function 2; LBD = Ligand binding domain.