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Updated: Jun 26, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
A Functional Survey of the Regulatory Landscape of Estrogen Receptor-Positive Breast Cancer Evolution
Iros Barozzi1, Neil Slaven2,3, Eleonora Canale2
1Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
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.
Insights
This study reveals how noncoding DNA changes drive endocrine therapy resistance in breast cancer. Exploiting transient cellular dependencies can hinder adaptive resistance mechanisms.
Area of Science:
- Genomics
- Cancer Biology
- Epigenetics
Background:
- Endocrine therapy resistance is a major cause of breast cancer relapse.
- Mechanisms driving resistance beyond known somatic alterations remain unclear.
- Noncoding DNA's role in cancer evolution under therapy is largely unexplored.
Purpose of the Study:
- To investigate the contribution of cis-regulatory elements (CREs) in noncoding DNA to endocrine therapy resistance.
- To dissect the functional roles of CREs in cancer cell adaptation and dormancy.
- To identify noncoding alterations associated with resistance in patient cohorts.
Main Methods:
- Functional genomics and epigenetic perturbation (CRISPRi) in vitro.
- Analysis of 12 megabases of noncoding DNA, including enhancers and promoters.
- Profiling of CRE somatic alterations in a longitudinal patient cohort undergoing endocrine therapy.
Main Results:
- CREs play context-dependent roles in dormancy entrance and endocrine therapy resistance.
- A limited set of noncoding somatic alterations were identified in patients resistant to therapy.
- Endocrine therapies induce transient cellular features that contribute to adaptive resistance.
Conclusions:
- Noncoding DNA alterations and changes in CRE usage are implicated in endocrine therapy resistance.
- Dormant breast cancer cells exhibit unique vulnerabilities that can be targeted.
- Exploiting transient dependencies offers a potential strategy to overcome adaptive resistance and reduce dormant persisters.
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