PO-355 Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer

Abstract

IntroductionBreast 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 (ERα) positive cells. ERα is central to BC pathogenesis and serves as the target of endocrine therapies (ET). ERα-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 methodsHere we show the results of a systematic investigation of the epigenetic landscape of ERα 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 ERα-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 discussionsWe mined promoters and enhancers from clinically relevant breast cancer samples for potential regulatory drivers identifying YY1 as a novel key player in ERα-positive BC. Finally, we demonstrate that epigenetic mapping can efficiently estimate phenotypic heterogeneity changes throughout BC progression.ConclusionCollectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.