Genetic and epigenetic driven variation in regulatory regions activity contribute to adaptation and evolution under endocrine treatment

Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation[1][1], [2][2], but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses[1][1], [3][3]–[9][4]. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis -regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers[10][5], gene promoters, and boundaries of topologically associating domains[11][6]. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance[12][7], [13][8] and endocrine therapy resistance[9][4]. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression. ### Competing Interest Statement R.L., I.A.M.B., M.B. and G.G.G. are employees of Novartis Pharma AG. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-9 [5]: #ref-10 [6]: #ref-11 [7]: #ref-12 [8]: #ref-13