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

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cam.issuedOnline2022-02-17
dc.contributor.authorAspros, Kirsten GM
dc.contributor.authorCarter, Jodi M
dc.contributor.authorHoskin, Tanya L
dc.contributor.authorSuman, Vera J
dc.contributor.authorSubramaniam, Malayannan
dc.contributor.authorEmch, Michael J
dc.contributor.authorYe, Zhenqing
dc.contributor.authorSun, Zhifu
dc.contributor.authorSinnwell, Jason P
dc.contributor.authorThompson, Kevin J
dc.contributor.authorTang, Xiaojia
dc.contributor.authorRodman, Esther PB
dc.contributor.authorWang, Xiyin
dc.contributor.authorNelson, Adam W
dc.contributor.authorChernukhin, Igor
dc.contributor.authorHamdan, Feda H
dc.contributor.authorBruinsma, Elizabeth S
dc.contributor.authorCarroll, Jason S
dc.contributor.authorFernandez-Zapico, Martin E
dc.contributor.authorJohnsen, Steven A
dc.contributor.authorKalari, Krishna R
dc.contributor.authorHuang, Haojie
dc.contributor.authorLeon-Ferre, Roberto A
dc.contributor.authorCouch, Fergus J
dc.contributor.authorIngle, James N
dc.contributor.authorGoetz, Matthew P
dc.contributor.authorHawse, John R
dc.contributor.orcidEmch, Michael J [0000-0001-8670-8138]
dc.contributor.orcidSun, Zhifu [0000-0001-8461-7523]
dc.contributor.orcidSinnwell, Jason P [0000-0003-1964-5522]
dc.contributor.orcidWang, Xiyin [0000-0002-3642-9373]
dc.contributor.orcidHamdan, Feda H [0000-0003-2455-2435]
dc.contributor.orcidJohnsen, Steven A [0000-0003-1198-5805]
dc.contributor.orcidHuang, Haojie [0000-0003-2751-6413]
dc.contributor.orcidIngle, James N [0000-0003-1257-7731]
dc.contributor.orcidGoetz, Matthew P [0000-0002-4383-270X]
dc.contributor.orcidHawse, John R [0000-0003-3406-470X]
dc.date.accessioned2022-03-22T02:01:04Z
dc.date.available2022-03-22T02:01:04Z
dc.date.issued2022-02-17
dc.date.updated2022-03-22T02:01:04Z
dc.description.abstractTriple 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.
dc.identifier.doi10.17863/CAM.82707
dc.identifier.eissn2374-4677
dc.identifier.issn2374-4677
dc.identifier.other35177654
dc.identifier.otherPMC8854734
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335275
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41523-022-00387-0
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101674891
dc.sourceessn: 2374-4677
dc.subject32 Biomedical and Clinical Sciences
dc.subject3211 Oncology and Carcinogenesis
dc.subjectBreast Cancer
dc.subjectCancer
dc.subject5.1 Pharmaceuticals
dc.subject2.1 Biological and endogenous factors
dc.subject2 Aetiology
dc.subject5 Development of treatments and therapeutic interventions
dc.subjectCancer
dc.titleEstrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer.
dc.typeArticle
dcterms.dateAccepted2022-01-21
prism.issueIdentifier1
prism.publicationNameNPJ Breast Cancer
prism.volume8
pubs.funder-project-idU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (F31CA228193, R01CA249116, PC50CA116201)
pubs.funder-project-idNCI NIH HHS (R01 CA249116, P50 CA116201, F31 CA228193)
pubs.funder-project-idCancer Research UK (20411)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41523-022-00387-0

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