Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 Hscore 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 down-regulator (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.

Original languageEnglish (US)
Pages (from-to)3802-3812
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

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Estrogen Receptor alpha
Ovarian Neoplasms
Tamoxifen
Heterografts
Therapeutics
Gene Expression
Transcriptome
Genes
Suspensions
Estrogens
Research Design
Cell Culture Techniques
Clinical Trials
Hormones

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Andersen, C. L., Sikora, M. J., Boisen, M. M., Ma, T., Christie, A., Tseng, G., ... Oesterreich, S. (2017). Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. Clinical Cancer Research, 23(14), 3802-3812. https://doi.org/10.1158/1078-0432.CCR-16-1501

Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. / Andersen, Courtney L.; Sikora, Matthew J.; Boisen, Michelle M.; Ma, Tianzhou; Christie, Alec; Tseng, George; Park, Yongseok; Luthra, Soumya; Chandran, Uma; Haluska, Paul; Mantia-Smaldone, Gina M.; Odunsi, Kunle; McLean, Karen; Lee, Adrian V.; Elishaev, Esther; Edwards, Robert P.; Oesterreich, Steffi.

In: Clinical Cancer Research, Vol. 23, No. 14, 15.07.2017, p. 3802-3812.

Research output: Contribution to journalArticle

Andersen, CL, Sikora, MJ, Boisen, MM, Ma, T, Christie, A, Tseng, G, Park, Y, Luthra, S, Chandran, U, Haluska, P, Mantia-Smaldone, GM, Odunsi, K, McLean, K, Lee, AV, Elishaev, E, Edwards, RP & Oesterreich, S 2017, 'Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens', Clinical Cancer Research, vol. 23, no. 14, pp. 3802-3812. https://doi.org/10.1158/1078-0432.CCR-16-1501
Andersen, Courtney L. ; Sikora, Matthew J. ; Boisen, Michelle M. ; Ma, Tianzhou ; Christie, Alec ; Tseng, George ; Park, Yongseok ; Luthra, Soumya ; Chandran, Uma ; Haluska, Paul ; Mantia-Smaldone, Gina M. ; Odunsi, Kunle ; McLean, Karen ; Lee, Adrian V. ; Elishaev, Esther ; Edwards, Robert P. ; Oesterreich, Steffi. / Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 14. pp. 3802-3812.
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AU - Andersen, Courtney L.

AU - Sikora, Matthew J.

AU - Boisen, Michelle M.

AU - Ma, Tianzhou

AU - Christie, Alec

AU - Tseng, George

AU - Park, Yongseok

AU - Luthra, Soumya

AU - Chandran, Uma

AU - Haluska, Paul

AU - Mantia-Smaldone, Gina M.

AU - Odunsi, Kunle

AU - McLean, Karen

AU - Lee, Adrian V.

AU - Elishaev, Esther

AU - Edwards, Robert P.

AU - Oesterreich, Steffi

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N2 - 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 Hscore 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 down-regulator (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.

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