Journal Article

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance

Li, Zheqi, Dowsett, Mitch, Buluwela, Laki, Patani, Neill, Martin, Lesley-Ann, Hills, Margaret, Poulogiannis, George, Simigdala, Nikiana, Thornhill, Allan, Ribas, Ricardo, Turgeon, Marc-Olivier, Pancholi, Sunil, Tenev, Tencho, Carroll, Jason, Fribbens, Charlotte, Harrod, Alison, Nikitorowicz-Buniak, Joanna, Sikora, Matthew J., Bhamra, Amandeep, Gao, Qiong, Zwart, Wilbert, Oesterreich, Steffi, Garcia-Murillas, Isaac, Schuster, Eugene, Gellert, Pascal, Turner, Nicholas, Martins, Vera, Ali, Simak

2017

Overview

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α ( ESR1 ) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance. ESR1 mutations occur in endocrine-resistant patients but have not yet been reported in in vitro models of breast cancer. Here, the authors report the discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in two breast cancer cell lines after acquisition of resistance to long-term-estrogen-deprivation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/1347 / 631/80/86/2363 / Biotechnology / Breast cancer / Breast Neoplasms - genetics / Cancer / Cell Line, Tumor / Deprivation / Drug Resistance, Neoplasm - genetics / Endocrine therapy / Estradiol - analogs & derivatives / Estradiol - therapeutic use / Estrogen Receptor alpha - genetics / Estrogen Receptor Antagonists - therapeutic use / Estrogen receptors / Estrogens / Female / Fulvestrant / Genomes / Humanities and Social Sciences / Humans / MCF-7 Cells / Metastases / multidisciplinary / Mutation / Science / Science (multidisciplinary) / Selective Estrogen Receptor Modulators - therapeutic use / Tamoxifen - therapeutic use / Tumor cell lines