Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer.

Authors
Aspros, Kirsten GM 
Carter, Jodi M 
Hoskin, Tanya L 
Suman, Vera J 
Subramaniam, Malayannan 

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Article
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Abstract

Triple Negative Breast Cancer (TNBC) accounts for 15-20% of all breast cancer cases, yet is responsible for a disproportionately high percentage of breast cancer mortalities. Thus, there is an urgent need to identify novel biomarkers and therapeutic targets based on the molecular events driving TNBC pathobiology. Estrogen receptor beta (ERβ) is known to elicit anti-cancer effects in TNBC, however its mechanisms of action remain elusive. Here, we report the expression profiles of ERβ and its association with clinicopathological features and patient outcomes in the largest cohort of TNBC to date. In this cohort, ERβ was expressed in approximately 18% of TNBCs, and expression of ERβ was associated with favorable clinicopathological features, but correlated with different overall survival outcomes according to menopausal status. Mechanistically, ERβ formed a co-repressor complex involving enhancer of zeste homologue 2/polycomb repressive complex 2 (EZH2/PRC2) that functioned to suppress oncogenic NFκB/RELA (p65) activity. Importantly, p65 was shown to be required for formation of this complex and for ERβ-mediated suppression of TNBC. Our findings indicate that ERβ+ tumors exhibit different characteristics compared to ERβ- tumors and demonstrate that ERβ functions as a molecular switch for EZH2, repurposing it for tumor suppressive activities and repression of oncogenic p65 signaling.

Publication Date
2022-02-17
Online Publication Date
2022-02-17
Acceptance Date
2022-01-21
Keywords
32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis, Cancer, Breast Cancer, 2 Aetiology, 2.1 Biological and endogenous factors, 5 Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Cancer
Journal Title
NPJ Breast Cancer
Journal ISSN
2374-4677
2374-4677
Volume Title
8
Publisher
Springer Science and Business Media LLC
Sponsorship
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (F31CA228193, R01CA249116, PC50CA116201)
NCI NIH HHS (R01 CA249116, P50 CA116201, F31 CA228193)
Cancer Research UK (20411)