American Association for Cancer Research
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10780432ccr161501-sup-166984_1_supp_3758584_xhfxdx.docx (86.02 kB)

Supplementary File 1 from Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens

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posted on 2023-03-31, 20:11 authored by Courtney L. Andersen, Matthew J. Sikora, Michelle M. Boisen, Tianzhou Ma, Alec Christie, George Tseng, Yongseok Park, Soumya Luthra, Uma Chandran, Paul Haluska, Gina M. Mantia-Smaldone, Kunle Odunsi, Karen McLean, Adrian V. Lee, Esther Elishaev, Robert P. Edwards, Steffi Oesterreich

Supplementary File 1 contains the genes included in the "EndoRx" NanoString code set.

Funding

NIH

Magee-Womens Research Foundation

University of Pittsburgh Cancer Institute

ARCS Foundation

Department of Defense

Ovarian Cancer Academy Early Career

RPCI

UPCI

Mayo Clinic

History

ARTICLE ABSTRACT

Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), 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 ERα target genes. Expression of this panel and ERα 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 ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα 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. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR.

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