The Role of Steroid Hormones, GREB1, and Reproductive Status in Ovarian Cancer Progression

Abstract

Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and 17-β estradiol accelerates tumour growth in mouse models of this disease. One possible mediator of estrogen action is Growth Regulation by Estrogen in Breast Cancer 1 (GREB1), an estrogen receptor alpha (ESR1)-upregulated protein. GREB1 is required for hormone-driven proliferation of several breast and prostate cancer cell lines, but its role in tumour progression is unknown and its mechanism of action remains unclear. To determine the role of GREB1 in ovarian cancer, its expression and function were examined in ovarian cancer cell lines and mouse models. GREB1 was upregulated by estradiol, and overexpression and/or knockdown of GREB1 showed that GREB1 promotes proliferation and migration in ovarian cancer cells. GREB1 knockdown also slowed tumour growth and prolonged survival in mice engrafted with ovarian cancer cells. GREB1 expression was detected in human ovarian tumours of all major histotypes, with moderate to strong expression in 75-85% of serous, endometrioid, mucinous, and clear cell carcinomas. GREB1 mRNA levels correlated with ESR1 transcripts, but protein levels of GREB1 and ESR1 did not show a correlation in tumours. Serous, endometrioid and mucinous ovarian cancers were almost always positive for either ESR1 or GREB1 (59/60 tumours), which may imply a dependence on estrogen signalling pathways. GREB1 expression in normal tissues is mainly confined to the reproductive tract, suggesting that it may be useful as a diagnostic biomarker. GREB1 combined with PAX8 showed high efficacy in differentiating mucinous tumours of gastrointestinal vs. ovarian origin. Targeting GREB1 may inhibit tumour-promoting pathways downstream of ESR1 and could therefore prove more effective than current anti-estrogen therapies.