PO-357 SREBP1 drives cell-autonomous cytoskeletal changes by KRT80 remodelling during ERα breast cancer progression

Abstract

microenvironment. Neutralising VEGF by avastin effectively abrogates metastasis induced by the ISX-BRD4 complex. In NSCLC carcinoma samples, significantly increased ISX expression was noted, correlating with distinct clinical metastatic features and poor prognosis. Conclusion These results suggest that the ISX-BRD4 axis mediates EMT signalling and exerts significant regulatory effects on tumour initiation and metastasis. Introduction Breast cancer (BC) is the most common cancer type and the second most frequent cause of cancer related death in women. 70% of all BC cases contain variable amounts of oestrogen receptor-alpha (ERa) positive cells. ERa is central to BC pathogenesis and serves as the target of endocrine therapies (ET). ERa-positive BC is typically subdivided in two 'intrinsic' molecular subtypes (luminal A and luminal B) characterised by distinct prognosis, highlighting functional inter-patient heterogeneity. Recent analyses demonstrate that patient-to-patient heterogeneity is more pervasive (reflected by histological, genetic architecture and transcriptional differences) ultimately influencing long-term response to endocrine treatment. Additionally, the presence of genetic intra-tumour heterogeneity has also now been extensively documented in several cancer types, demonstrating the role of clonal evolution in cancer. Parallel to genetic evolution, phenotypic/functional changes driven by epigenetic mechanisms can also contribute to breast cancer progression and ET resistance in cell lines. Nevertheless, little is known about the epigenome of BC patients, its influence on intra-tumour phenotypic heterogeneity and its role in breast cancer progression. Material and methods Here we show the results of a systematic investigation of the epigenetic landscape of ERa positive primary and metastatic breast cancer from 47 individuals. Our results represent the first large scale topographic mapping of the active regulatory landscape of longitudinal ERa-positive BC. Using H3K27ac we mapped active promoters and enhancers across treatment naïve primary and endocrine treated metastatic patients. We used bioinformatic approaches to deconvolute the complex regulatory landscape and identified inter-and intra-patient epigenetic heterogeneity. Results and discussions We mined promoters and enhancers from clinically relevant breast cancer samples for potential regulatory drivers identifying YY1 as a novel key player in ERapositive BC. Finally, we demonstrate that epigenetic mapping can efficiently estimate phenotypic heterogeneity changes throughout BC progression. Conclusion Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients. PO-355