Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW7 3RP, UK.
Division of Cancer, CRUK Labs, University of London Imperial College, London, W12 0NN, UK.
Nat Commun. 2017 Nov 30;8(1):1865. doi: 10.1038/s41467-017-01864-y.
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 and ESR1 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.
内分泌治疗耐药仍是乳腺癌的一个主要临床问题。遗传研究强调了雌激素受体-α（ESR1）突变的潜在作用，这些突变在转移性、内分泌耐药的情况下更为常见。在获得内分泌耐药之前或之后，在体外 BC 模型中均未报道过天然存在的 ESR1 突变，因此很难研究其功能后果。我们报告了第一个在 MCF7 和 SUM44 ESR1 阳性细胞系中发现天然存在的 ESR1 和 ESR1 突变，这些细胞系在长期雌激素剥夺（LTED）耐药和随后对氟维司群（ICIR）耐药后被富集。突变随时间而增加，影响 ESR1 与基因组的结合，并改变了 ESR1 相互作用组。这些结果强调了这些突变的重要性和功能后果，并为研究内分泌耐药提供了重要资源。
