Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

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 ERα and endocrine responsiveness. Assessing ERα 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.

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

“…Our data showed that estrogen metabolism did not correlate with ESR1, ESR2, and ESRRG expression. This is supported by a previous paper by Andersen et al [48], showing that approximately 80% of HGSOC tumor samples express ESR1; however, the response to an antiestrogenic therapy in patients is rather poor. This group also reported that the ERα status in HGSOC cells is not a sufficient tool to predict the response to an antiestrogenic therapy.…”

E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness

“…For example, epidemiological studies found that women treated with hormone replacement therapy had an increased risk of ovarian cancer . However, antiestrogen therapy was only somewhat effective for a subset of ovarian cancer patients, regardless of ER‐α expression status …”

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…[ 12a ] It is an effective strategy that the precise oncology models corroborate intertumor heterogeneity to identify the key genes closely associated with clinical response. [ 15 ]…”