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Contrasting activities of estrogen receptor beta isoforms in triple negative breast cancer

Abstract

Purpose

Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, lacks the three major receptors for predicting outcome or targeting therapy. Hence, our aim was to evaluate the potential of estrogen receptor beta (ERβ) as a possible endocrine therapy target in TNBC.

Methods

The expression and prognostic effect of ERβ isoforms were analyzed using TCGA breast tumor data, and the expression of ERβ isoform mRNA and protein in TNBC cell lines was assayed. Endogenous ERβ2 and ERβ5 were knocked down with siRNA, and ERβ2, ERβ5, and ERβ1 were upregulated using a doxycycline-inducible lentiviral system. Cell proliferation, migration and invasion, and specific gene expressions were evaluated.

Results

ERβ2 and ERβ5 were the predominant endogenous forms of ERβ in TNBC tumors and cell lines. High ERβ2 predicted worse clinical outcome. Knockdown of endogenous ERβ2/ERβ5 in cell lines suppressed proliferation, migration and invasion, and downregulated proto-oncogene survivin expression. ERβ2/ERβ5 upregulation did the reverse, increasing survivin and these cell activities. ERβ1 was barely detectable in TNBC cell lines, but its upregulation reduced survivin, increased tumor suppressor expression (E-cadherin and cystatins), and suppressed proliferation, migration and invasion in both ligand-independent and dependent manners, suggesting the possible translational benefit of ERβ ligands.

Conclusions

ERβ2/ERβ5 and ERβ1 exhibit sharply contrasting activities in TNBC cells. Our findings imply that delineating the absolute amounts and relative ratios of the different ERβ isoforms might have prognostic and therapeutic relevance, and could enable better selection of optimal approaches for treatment of this often aggressive form of breast cancer.

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Acknowledgements

This research was supported by grants from the Breast Cancer Research Foundation (BCRF-084 to JAK and BSK and BCRF-083 to BSK) and the NIH/NCI (1R01 CA220284 to BSK and JAK). SY was a Visiting Scholar supported in part by 345 Talent Project from Shengjing Hospital of China Medical University. XJ was a Visiting Scholar supported in part by a fellowship from Shenyang Chest Hospital, Shenyang, China. We thank Dr. Dorraya El-Ashry of the University of Minnesota for kindly providing DT28 cells.

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Correspondence to Benita S. Katzenellenbogen.

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JAK is a stockholder of Radius Health, Inc. BSK and JAK have ownership interest in Celcuity, Inc. The other authors declare that they have no conflict of interest.

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Yan, S., Dey, P., Ziegler, Y. et al. Contrasting activities of estrogen receptor beta isoforms in triple negative breast cancer. Breast Cancer Res Treat 185, 281–292 (2021). https://doi.org/10.1007/s10549-020-05948-0

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Keywords

  • Estrogen receptor beta (ERβ)
  • Triple negative breast cancer (TNBC)
  • Migration
  • Invasion
  • Proliferation