A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution.

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cd-23-1157.pdf (17.51 MB)

Embargo End Date

ICR Authors

Chambers, Alfie
 Magnani, Luca

Authors

Barozzi, I
Slaven, N
Canale, E
Lopes, R
Amorim Monteiro Barbosa, I
Bleu, M
Ivanoiu, D
Pacini, C
Mensa', E
Chambers, A
Bravaccini, S
Ravaioli, S
Győrffy, B
Dieci, MV
Pruneri, G
Galli, GG
Magnani, L

Document Type

Journal Article

Date

2024-09-04

Date Accepted

2024-05-14

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.

Citation

Cancer Discovery, 2024, pp. OF1 - OF19

DOI

10.1158/2159-8290.CD-23-1157
10.1158/2159-8290.CD-23-1157

URI

https://repository.icr.ac.uk/handle/internal/6355

Rights

https://creativecommons.org/licenses/by-nc-nd/4.0/

Source Title

Cancer Discovery

Publisher

AMER ASSOC CANCER RESEARCH

ISSN

2159-8274

eISSN

2159-8290
2159-8290

Collections

Breast Cancer Research

Research Team

Breast Epige Plast & Evol

Notes