Department of Medicine, Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Cell Rep. 2018 Aug 7;24(6):1434-1444.e7. doi: 10.1016/j.celrep.2018.07.009.
RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.
RNA 测序（RNA-seq）在雌激素受体阳性（ER）乳腺癌中检测到雌激素受体α基因（ESR1）融合转录本，但它们在疾病发病机制中的作用仍不清楚。我们研究了多种 ESR1 融合，并发现其中两种融合均在晚期内分泌治疗耐药疾病中发现，可编码稳定且功能正常的融合蛋白。在这两种情况下，ESR1-e6>YAP1 和 ESR1-e6>PCDH11X，ESR1 外显子 1-6 与伴侣基因的 C 末端序列发生框内融合。功能特性包括雌激素非依赖性生长、ER 靶基因的组成性表达和抗雌激素耐药性。这两种融合均激活与转移相关的转录程序，诱导细胞迁移，并促进肺转移的发展。ESR1-e6>YAP1 和 ESR1-e6>PCDH11X 诱导的生长仍然对 CDK4/6 抑制剂敏感，并且天然表达 ESR1-e6>YAP1 融合的患者来源异种移植（PDX）也有反应。因此，转录活性的 ESR1 融合既引发内分泌治疗耐药性，又引发转移进展，尽管预测 CDK4/6 抑制剂治疗有效，但这可以解释与致命疾病进展的关联。
