Active estrogen receptor-alpha signaling in ovarian cancer

High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ER) in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, ER has been understudied as a target in this disease. Results: Proliferation is ER-regulated in HGSOC cells in vitro and in vivo, and is in part dependent on 3-D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ER targets. The selective ER down-regulator (SERD) fulvestrant is more effective than tamoxifen in blocking ER action. ER H-score was predictive of efficacy of endocrine therapy, and this prediction could be further improved by inclusion of target gene expression, especially that of IGFBP3. Conclusion: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ER and endocrine responsiveness. Assessing ER function (e.g. IGFBP3 expression) in conjunction with ERH-score may help select patients who would benefit from endocrine therapy. Our preclinical data suggest that SERDs might be more effective than tamoxifen. PEO1 and PEO4 ovarian cancer cells were hormone-deprived in IMEM + 10% charcoal stripped esrum for three days. After deprivation, cells were treated with vehicle (EtOH), 1 nM estradiol (E2), 1 uM 4-hydroxytamoxifen (Tam), 1 uM ICI182,780 (ICI), Tam + E2, or ICI + E2 for 3 hours. Cells were lysed and RNA isolated usin gthe Illustra RNAspin Mini kit (GE).