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Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors

Breast Cancer Research and Treatment volume 181, pages 297–307 (2020)Cite this article

Abstract

Purpose

Many human breast tumors become resistant to endocrine therapies and recur due to estrogen receptor (ERα) mutations that convey constitutive activity and a more aggressive phenotype. Here, we examined the effectiveness of a novel adamantyl antiestrogen, K-07, in suppressing the growth of breast cancer metastases containing the two most frequent ER-activating mutations, Y537S and D538G, and in extending survival in a preclinical metastatic cancer model.

Methods

MCF7 breast cancer cells expressing luciferase and Y537S or D538G ER were injected into NOD-SCID-gamma female mice, and animals were treated orally with the antiestrogen K-07 or control vehicle. Comparisons were also made with the antiestrogen Fulvestrant. The development of metastases was monitored by in vivo bioluminescence imaging with phenotypic characterization of the metastases in liver and lung by immunohistochemical and biochemical analyses.

Results

These breast cancer cells established metastases in liver and lung, and K-07 treatment reduced the metastatic burden. Mice treated with K-07 also survived much longer. By day 70, only 28% of vehicle-treated mice with mutant ER metastases were alive, whereas all K-07-treated D538G and Y537S mice were still alive. K-07 also markedly reduced the level of metastatic cell ER and the expression of ER-regulated genes.

Conclusion

The antiestrogen K-07 can reduce in vivo metastasis of breast cancers and extend host survival in this preclinical model driven by constitutively active mutant ERs, suggesting that this compound may be suitable for further translational examination of its efficacy in suppression of metastasis in breast cancers containing constitutively active mutant ERs.

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Data availability

All data generated or analyzed in this study are available from the corresponding author on reasonable request.

Abbreviations

ER:

Estrogen receptor α

IHC:

Immunohistochemistry

NSG:

NOD-SCID-gamma

SERM:

Selective estrogen receptor modulator

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Funding

This research was supported by grants from the Breast Cancer Research Foundation (BCRF-083 to BSK and BCRF-084 to JAK and BSK), IIDRP-16-006 to BHP, NIH/NCI Grant 1R01CA220284 (to BSK, JAK, and KWN), Susan G. Komen SAC 170079 to BHP, and NIH Grant R01CA234025 and DOD Breast Cancer Research Program Grant BC171214 to ERN.

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Mary J. Laws, Yvonne Ziegler, Sayyed Hamed Shahoei, Parama Dey, Mayuri Yasuda, Erik R. Nelson & Benita S. Katzenellenbogen

  2. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Sung Hoon Kim & John A. Katzenellenbogen

  3. Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    John A. Katzenellenbogen, Erik R. Nelson & Benita S. Katzenellenbogen

  4. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Erik R. Nelson & Benita S. Katzenellenbogen

  5. Vanderbilt University Ingraham Cancer Center, Nashville, TN, 37232, USA

    Ben Ho Park

  6. The Scripps Research Institute, Jupiter, FL, 33458, USA

    Kendall W. Nettles

Authors
  1. Mary J. Laws
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Corresponding author

Correspondence to Benita S. Katzenellenbogen.

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Conflict of interest

JAK is a consultant and stockholder of Radius Health, Inc. BSK and JAK have ownership interest in Celcuity, Inc. Patent applications covering K-07 that include JAK, SHK, and BSK as inventors have been filed by the University of Illinois. BHP receives royalties from Horizon Discovery, LTD, was a scientific advisory board member for Loxo Oncology and had ownership interest in Loxo Oncology, was a paid consultant for Foundation Medicine, Inc., H3 Biomedicine, Casdin Capital, Roche, Eli Lilly, Astra Zeneca, is an unpaid consultant for Tempus, and is a paid consultant for Jackson Laboratories, Celcuity, Pathovax, with ownership interest in Celcuity, and has research contracts with Abbvie, Foundation Medicine Inc. and Pfizer. The other authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were performed in accordance with institutional protocols and approved by the University of Illinois Institutional Animal Care and Use Committee (PHS Assurance: D16-00,075 (A3118-01)). This article does not contain any studies with human participants performed by any of the authors.

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Mary J. Laws and Yvonne Ziegler are co-first authors.

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Laws, M.J., Ziegler, Y., Shahoei, S.H. et al. Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors. Breast Cancer Res Treat 181, 297–307 (2020). https://doi.org/10.1007/s10549-020-05629-y

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  • DOI: https://doi.org/10.1007/s10549-020-05629-y

Keywords

  • Antiestrogen
  • Estrogen receptor
  • Metastasis
  • Breast cancer