Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling

AbstractBreast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.

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Identification of new therapeutic leads for triple negative breast cancer subtypes

Planta Medica ◽

10.1055/s-0035-1556254 ◽

2015 ◽

Vol 81 (11) ◽

Author(s):

AJ Robles ◽

L Du ◽

S Cai ◽

RH Cichewicz ◽

SL Mooberry

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Cancer Subtypes ◽

Therapeutic Leads

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Faculty Opinions recommendation of Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13405017.14775138 ◽

2011 ◽

Author(s):

Thomas Egelhoff

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Preclinical Models ◽

Cancer Subtypes ◽

Selection Of

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Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Journal of Clinical Investigation ◽

10.1172/jci45014 ◽

2011 ◽

Vol 121 (7) ◽

pp. 2750-2767 ◽

Cited By ~ 2406

Author(s):

Brian D. Lehmann ◽

Joshua A. Bauer ◽

Xi Chen ◽

Melinda E. Sanders ◽

A. Bapsi Chakravarthy ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Preclinical Models ◽

Cancer Subtypes ◽

Selection Of

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Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13164139 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4139

Author(s):

Pere Llinàs-Arias ◽

Sandra Íñiguez-Muñoz ◽

Kelly McCann ◽

Leonie Voorwerk ◽

Javier I. J. Orozco ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Regulatory Elements ◽

Her2 Overexpression ◽

Breast Cancers ◽

Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

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