Slaven, Neil, Marques Lopes, Rui Filipe, Canale, Eleonora, Ivanoiu, Diana, Pacini, Claudia, Barbosa, Ines, Bleu, Melusine, Bravaccini, Sara, Ravaioli, Sara, Dieci, Maria Vittoria, Pruneri, Giancarlo, Galli, Giorgio, Barozzi, Iros and Magnani, Luca (2024) A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution. Cancer discovery, 14 (9). pp. 1612-1630. ISSN 2159-8290

Abstract

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

Item Type:	Article
Keywords:	Humans Breast Neoplasms Female Receptors, Estrogen Gene Expression Regulation, Neoplastic Drug Resistance, Neoplasm Antineoplastic Agents, Hormonal
Date Deposited:	12 Oct 2024 00:45
Last Modified:	12 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/46823