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Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies

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Abstract

Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients.

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Funding

This work was supported by the American Cancer Society Research Scholar Grant RSG-19–194-01-CSM (OS), National Institutes of Health Grant 2P20GM109091-06 (OS), and Susan G. Komen Interdisciplinary Graduate Training to Eliminate Cancer Disparities (IGniTE-CD) GTDR17500160 (OzgeS).

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  1. Department of Drug Discovery and Biomedical Sciences, University of South Carolina, 715, Sumter Street, CLS609D, Columbia, SC, 29208, USA

    Ozge Saatci, Kim-Tuyen Huynh-Dam & Ozgur Sahin

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  1. Ozge Saatci
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  2. Kim-Tuyen Huynh-Dam
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  3. Ozgur Sahin
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Contributions

Conception and design: OS; literature search and collection of the scientific information: O.Saatci and KH; writing, review and/or revision of the manuscript: O.Saatci and KH; critical revision and editing of the article for important intellectual content and final approval: OS.

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Correspondence to Ozgur Sahin.

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O. Sahin is co-founder of OncoCube Therapeutics LLC; founder and president of LoxiGen, Inc.; and is also a recipient of a research grant from Halozyme Therapeutics, Inc. The other authors declare that they have no conflict of interest.

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Saatci, O., Huynh-Dam, KT. & Sahin, O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J Mol Med 99, 1691–1710 (2021). https://doi.org/10.1007/s00109-021-02136-5

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  • DOI: https://doi.org/10.1007/s00109-021-02136-5

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