Abstract

Epithelial-to-Mesenchymal Transition (EMT), a process by which epithelial cells lose their cell polarity and gain mesenchymal cell phenotype, is believed to be a major contributor to the development of metastases. The functional contribution of this concept, although established in experimental cancer models, is not evident in human tumour samples fueling an ongoing debate. EMT is controlled by multiple molecular mechanisms including alternative splicing. Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) regulate the splicing programme of EMT by promoting “epithelial-ness”. Here we show that ESRP1 is not only required to maintain the epithelial nature and tumour growth of ER+ breast cancers but high levels, rather than low, are observed in patients with aggressive tumours and associated with endocrine resistance in multiple cohorts. We confirm the ESRP1 mediated “epithelial-ness” splicing program is active in these aggressive tumours. Our data highlights, for the first time, the invasivness in human ER+ breast cancers is independent of EMT. We further