Activating ESR1 mutations in hormone-resistant metastatic breast cancer

By D. Robinson, Yi-Mi Wu, P. Vats, Fengyun Su, R. Lonigro, Xuhong Cao, Shanker Kalyana-Sundaram, Rui Wang, Yu Ning, L. Hodges and 15 more. Nature Genetics, 2013

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Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.

Subfields: Genetics, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/61c97c7f3a6deaa65f738e7f95cabbe8f351e0d7

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Citations in the corpus

Signal transduction in cancer. (2015, neutral): “Disruption of the balance between ERa and ERb or mutations in ERa that yield truncated proteins or activated proteins can dysregulate this pathway (Thomas and Gustafsson 2011; Li et al. 2013; Robinson et al. 2013; Toy et al. 2013).”
Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “As previously reported, ESR1 resistancemutations were found in five patients previously treated with endocrine therapies (Chandarlapaty et al., 2016; Robinson et al., 2013; Toy et al., 2013) and predicted progressive disease upon switching treatment (Figure S5).”
The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers (2018, background): “On the other hand, and reflecting the impact of prior therapy, ligand binding domain mutations in ESR1 were present in 18% of HRHER2 patients whose sequenced tumor specimens were collected after endocrine therapy (n = 128 of 692) (Chandarlapaty et al., 2016; Fribbens et al., 2016; Robinson et al., 2”
Explaining by Removing: A Unified Framework for Model Explanation (2020, methodology): “We observe that most explanations identify the same gene as being most important (ESR1), but, besides this, the explanations are difficult to compare qualitatively.”
Overcoming Endocrine Resistance in Breast Cancer (2020, positive): “Stable ESR1 in-frame gene fusions were first reported in 2013 (Li et al., 2013) and have since been found in at least 1% of MBCs (usually in tumors resistant to endocrine therapy) (Hartmaier et al., 2018), although the frequency is likely higher considering capture-based targeted exon sequencing oft”