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The search for ESR1 mutations in breast cancer

Nature Genetics volume 45, pages 1415–1416 (2013)Cite this article

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Two new studies report the identification of activating ESR1 gene mutations in aromatase inhibitor–resistant metastatic breast cancers. This insight into therapeutic resistance suggests new approaches that may be useful in the management of endocrine-resistant breast cancer.

For nearly four decades, blockade of estrogen receptor α (ERα) action has been a successful treatment strategy for women with breast cancers expressing ER. Unfortunately, de novo or acquired resistance to endocrine therapy is common. Mutations affecting ER have been proposed as a possible mechanism for this resistance, but ESR1 mutations were found to be infrequent in primary breast cancer. Indeed, in sequencing 390 primary cancers positive for ER expression (ER+), The Cancer Genome Atlas Research Network did not identify any ESR1 mutations1. Given the relevance of ER for the development and progression of breast cancer, identifying the mechanism of resistance to endocrine therapy is an important problem to solve. A clue to the underlying mechanism surfaced recently in a report by Matthew Ellis and colleagues2 that described the identification of ESR1 mutations in xenografts derived from primary or metastatic breast cancers that were resistant to aggressive treatment. Now, two independent studies in this issue by Arul Chinnaiyan and colleagues3 and Sarat Chandarlapaty and colleagues4 show that activating ESR1 mutations are relatively frequent events in advanced ER+ hormone-resistant breast cancer, particularly in metastatic lesions from women who took estrogen-lowering drugs such as aromatase inhibitors.

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Figure 1: Identification of ESR1 mutations in metastatic breast cancer.

Katie Vicari

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Authors and Affiliations

  1. Steffi Oesterreich and Nancy E. Davidson are in the Department of Pharmacology and Chemical Biology and Department of Medicine, University of Pittsburgh, Women's Cancer Research Center, University of Pittsburgh Cancer Institute and UPMC Cancer Center, and Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.,

    Steffi Oesterreich & Nancy E Davidson

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  1. Steffi Oesterreich
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  2. Nancy E Davidson
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Correspondence to Nancy E Davidson.

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Oesterreich, S., Davidson, N. The search for ESR1 mutations in breast cancer. Nat Genet 45, 1415–1416 (2013). https://doi.org/10.1038/ng.2831

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