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Tumor Heterogeneity Confounds and Illuminates: A case for Darwinian tumor evolution

Nature Medicine volume 20, pages 344–346 (2014)Cite this article

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Ovarian hormones such as estrogens play a key part in normal mammary gland development and in breast tumorigenesis. Estrogens mediate their action on mammary epithelial cells via estrogen receptor (ER), a ligand-dependent nuclear steroid hormone receptor encoded by the ESR1 gene. Because the majority (∼70%) of human breast tumors are ER positive and depend on estrogen for growth, the use of selective ER modulators, such as tamoxifen, in ER-expressing tumors was one of the first examples for successful targeted therapy based on the molecular classification of tumors1. Better understanding of ER function led to the development of multiple other targeted agents with different mechanisms of action, allowing for the more effective inhibition of the ER signaling pathway and fewer side effects. Unfortunately, about a third of ER-positive breast cancers are inherently resistant to endocrine therapy, although they may still respond to other drugs with different mechanisms of action, and 30–40% of the initial responders will also eventually progress to resistant disease. Because the options for these patients are limited, understanding what induces endocrine resistance in these tumors has been one of the longest standing and most intense areas of breast cancer research.

Multiple molecular alterations have been shown to mediate endocrine resistance through different mechanisms including activation of kinase signaling pathways, altered expression of cell cycle regulators, overexpression of ER coactivators, intratumor heterogeneity of ER, and activation of epithelial to mesenchymal transition (EMT)2. Contrary to findings with resistance to other types of targeted therapies, genetic alterations in the target itself, ESR1, have not been found. And although rare ESR1 mutations have been found in human breast and endometrial carcinomas, most of these have unclear functional relevance3,4 or are thought to be too infrequent to explain the major fraction of endocrine resistance5. Even the Cancer Genome Atlas Research Network (TCGA) failed to identify ESR1 mutations in recent comprehensive breast-cancer-genome sequencing human studies6. Nonetheless, this all changed in the past few months with a flurry of papers reporting common mutations in ESR1 ligand-binding domain in endocrine-resistant metastatic human breast carcinomas, implying a direct role for these mutations in therapeutic resistance7,8,9,10,11.

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Figure 1: The role of ESR1 mutations in breast cancer endocrine resistance.

Katie Vicari

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  1. Kornelia Polyak is at the Department of Medical Oncology, and Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,

    Kornelia Polyak

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Correspondence to Kornelia Polyak.

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Polyak, K. Tumor Heterogeneity Confounds and Illuminates: A case for Darwinian tumor evolution. Nat Med 20, 344–346 (2014). https://doi.org/10.1038/nm.3518

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