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Hormonal modulation of ESR1 mutant metastasis

Oncogene volume 40, pages 997–1011 (2021)Cite this article

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A Correction to this article was published on 15 November 2021

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Abstract

Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial–mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E2) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E2; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.

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Fig. 1: The Y537S ESR1 mutant becomes the predominant cell type in vivo.
Fig. 2: Y537S ESR1 mutants exhibit an EMT phenotype.
Fig. 3: Tam treatment blocked metastasis in ESR1 mutant tumors.
Fig. 4: The Y537S ESR1 mutant signature is prognostic of patient outcomes.
Fig. 5: AR agonist treatment blocked Y537S mutant metastasis.
Fig. 6: DHT treatment regulates mutant EMT gene expression through the ER cistrome.

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Acknowledgements

The authors would like to thank Drs. Chandandeep Nagi for his pathology expertise and Sasha Pejerrey for initial edits of the paper. We acknowledge the joint participation with the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with BCM and the Cancer Program. We acknowledge the joint collaboration with WFS through the CPRIT MIRA grant mechanism.

Funding

Breast Cancer Research Foundation BCRF 19-055, NIH R01 CA207270, NIH R01CA072038, Cancer Prevention Institute of Texas CPRIT MIRA (Kelly Hunt, PI) to SAWF; Adrienne Helis Malvin Medical Research Foundation Cancer Program M-2017 to CEF; P30 CA125123-05 Dan L Duncan Cancer Center Cell-based assay screening core; Translational Breast Cancer Research Training Program T32-CA203690-02; Predoctoral Institutional Research Training Grant (T32) Training Grant 5T32GM008231-30; T32 2389301302, Cancer Prevention Institute of Texas (CPRIT) RP170005; NIEHS grants P30 ES030285, P42 ES027725; U01 CA217842, Susan G. Komen Breast Cancer Foundation SAC110052, Breast Cancer Research Foundation BCRF‐19-110. Grant number RP180712/CPRIT-MIRA.

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Authors and Affiliations

  1. Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Guowei Gu, Sarah K. Herzog, Yassine Rechoum, Jin-Ah Kim, Derek Dustin, Hin Ching Lo, Amanda R. Beyer, David G. Edwards, Thomas Gonzalez, Anna Tsimelzon, Susan G. Hilsenbeck, Alyssa Alaniz, Xiang H. -F. Zhang & Suzanne A. W. Fuqua

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Guowei Gu, Xiang H. -F. Zhang, Charles E. Foulds & Suzanne A. W. Fuqua

  3. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy

    Guowei Gu, Luca Gelsomino & Sebastiano Andò

  4. Cancer Biology & Genetics Program Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Lin Tian

  5. Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX, USA

    Sarah K. Herzog

  6. Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA

    Meng Gao

  7. Department of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lili Du & W. Fraser Symmans

  8. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA

    Derek Dustin

  9. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Helen J. Huang & Filip Janku

  10. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

    Natalie M. Fernandez, Dan Liu & Jun Xu

  11. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Sandra L. Grimm, Susan G. Hilsenbeck, Xiang H. -F. Zhang, Cristian Coarfa, Charles E. Foulds & Suzanne A. W. Fuqua

  12. Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA

    Shunqiang Li

  13. Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

    Gordon B. Mills

  14. Eugene McDermott Center for Human Growth and Development and Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA

    Ralf Kittler

  15. Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA

    Charles E. Foulds

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  1. Guowei Gu
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Contributions

Conception and design: GG, SAWF. Development of methodology: GG, LT, DL, SKH, CC. Acquisition of data: GG, SKH, HCL, TG, YR, RK, LD, ARB, MG, DD, LG, J-AK, HJH, NMF, JX, AA, CEF, DGE, SLG. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, and computation analysis): GG, SAWF, LT, TG, AT, SGH, CC, SLG, SKH, WFS. Writing, review, and/or revision of the paper: GG, SAWF, TG, ARB. Administrative, technical, or material support: ARB, SA, SL, GBM, FJ, XH-FZ. Study supervision: SAWF, GG.

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Correspondence to Suzanne A. W. Fuqua.

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Conflict of interest

(1) CEF discloses: an equity position in Coactigon, Inc. (2) FJ discloses: (a) Grant/Research Funding (Institutional): Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb; (b) Scientific Advisory Board: Deciphera, IFM Therapeutics, Synlogic, Guardant Health, Ideaya, PureTech Health; (c) Paid Consultant: Trovagene, Immunomet, Jazz Pharmaceuticals, Sotio; (d) Ownership Interests: Trovagene. (3) GBM discloses: (a) SAB/Consultant: AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, Zentalis Pharmaceuticals; (b) Stock/Options/Financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda; (c) Licensed Technology: HRD assay to Myriad Genetics, DSP patents with Nanostring. (4) SL discloses: (a) The Washington Unversity PDX development and trial center is supported by NIH 3U54CA224083-02S3. (b) SL has received license fee from Envigo. He received research funding from Pfizer, Takeda Oncology, and Zenopharm, outside of this project.

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Gu, G., Tian, L., Herzog, S.K. et al. Hormonal modulation of ESR1 mutant metastasis. Oncogene 40, 997–1011 (2021). https://doi.org/10.1038/s41388-020-01563-x

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