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Andersen CL, Sikora MJ, Boisen MM, Ma T, Christie A, Tseng G, Park YS, Luthra S, Chandran U, Haluska P, Mantia-Smaldone G, Odunsi K, McLean K, Lee AV, Elishaev E, Edwards RP, Oesterreich S
Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens
Clin Cancer Res (2017) 23:3802-3812.
Abstract
PURPOSE: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, estrogen receptor-alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, estrogen receptor-alpha-dependent HGSOC. EXPERIMENTAL DESIGN: We characterized endocrine response in HGSOC cells across culture conditions (2-D, 3-D, forced suspension) and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of estrogen receptor-alpha target genes. Expression of this panel and estrogen receptor-alpha H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response. RESULTS: Proliferation is estrogen receptor-alpha-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3-D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as estrogen receptor-alpha targets. The selective estrogen receptor-alpha down-regulator (SERD) fulvestrant is more effective than tamoxifen in blocking estrogen receptor-alpha action. Estrogen receptor-alpha H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3. CONCLUSIONS: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional estrogen receptor-alpha and endocrine responsiveness. Assessing estrogen receptor-alpha function (e.g. IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen.
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Publication Date: 2017-07-15.
PMCID: PMC5503796
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Last updated on Thursday, November 02, 2017