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Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

A Correction to this article was published on 16 March 2020

This article has been updated

Abstract

Purpose

Studies have identified several estrogen receptor α (ERα) ligand-binding domain (LBD) somatic mutations in endocrine therapy resistant, metastatic ER-positive breast cancers. The most common mutations, Tyr537Ser (Y537S) and Asp538Gly (D538G), are detected in ~ 30% of endocrine resistant metastatic breast cancer patients. These ESR1 mutations induce the agonist conformation of ERα, confer an estrogen-independent phenotype, and promote drug resistance to antiestrogens.

Methods

ER-positive, estrogen-dependent MCF-7 cells were engineered to express either the Y537S or D538G mutants using CRISPR knock-in (cY537S and cD538G). These cells were used to screen several estrogen receptor degrader (ERD) compounds synthesized using the Proteolysis Targeting Chimeras (PROTAC) method to induce degradation of ERα via the ubiquitin–proteasome pathway.

Results

Wild-type MCF-7 and ERα LBD mutant cells were treated with ERD-148 (10 pM–1 µM) and assayed for cellular proliferation using the PrestoBlue cell viability assay. ERD-148 attenuated ER-dependent growth with IC50 values of 0.8, 10.5, and 6.1 nM in MCF-7, cY537S, and cD538G cells, respectively. Western blot analysis showed that MCF-7 cells treated with 1 nM ERD-148 for 24 h exhibited reduced ERα protein expression as compared to the mutants. The ER-regulated gene, GREB1, demonstrated significant downregulation in parental and mutant cells after 24 h of ERD-148 treatment at 10 nM. Growth of the ER-negative, estrogen-independent MDA-MB-231 breast cancer cells was not inhibited by ERD-148 at the ~ IC90 observed in the ER-positive cells.

Conclusion

ERD-148 inhibits the growth of ER-positive breast cancer cells via downregulating ERα with comparable potency to Fulvestrant with marginal non-specific toxicity.

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Change history

  • 16 March 2020

    In the original publication of the article, the spelling of the sixth author’s given name was incorrect. The corrected author name should read as “Wadie David”. The original article has been corrected.

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Acknowledgements

The authors would like to thank the University of Michigan Biomedical Research Sequencing Core for their support. We acknowledge the assistance provided by the GUMC Tissue Culture Shared Resource, which is supported in part by the Lombardi Comprehensive Cancer Center support grant (NIH/NCI Grant P30-CA051008).

Funding

Research reported in this publication was supported in part by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number T32ES007062 (TLG), the Breast Cancer Research Foundation (BCRF) (N003173 to JMR), and the University of Michigan Rogel Cancer Center Breast Strategic Fund (JMR, SW, and DFH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA

    Thomas L. Gonzalez

  2. The University of Michigan Rogel Cancer Center, Ann Arbor, USA

    Molly Hancock, Christina L. Gersch, Jose M. Larios, Wadie David, Jiantao Hu, Daniel F. Hayes, Shaomeng Wang & James M. Rae

  3. Department of Internal Medicine, University of Michigan Medical School, 6310 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA

    Molly Hancock, Christina L. Gersch, Jose M. Larios, Wadie David, Jiantao Hu, Daniel F. Hayes, Shaomeng Wang & James M. Rae

  4. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, USA

    Siqi Sun, Shaomeng Wang & James M. Rae

  5. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA

    Shaomeng Wang

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Correspondence to James M. Rae.

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Conflict of interest

The University of Michigan has filed a patent application on ERD-148 and its related ER degraders. S.W. and J.H. are co-inventors on the patent application, which has been licensed to Oncopia Therapeutics, Inc. S.W. is a co-founder of Oncopia and a paid consultant. S.W. and the University of Michigan own stock in Oncopia. The University of Michigan has received a research contract from Oncopia for which S.W. serves as the principal investigator.

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The original version of this article was revised: The spelling of the sixth author’s given name was incorrectly published. The author name was corrected.

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Gonzalez, T.L., Hancock, M., Sun, S. et al. Targeted degradation of activating estrogen receptor α ligand-binding domain mutations in human breast cancer. Breast Cancer Res Treat 180, 611–622 (2020). https://doi.org/10.1007/s10549-020-05564-y

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