Active estrogen receptor-alpha signaling in ovarian cancer. Homo sapiens

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. Overall design: 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).