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Article: FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer

TitleFOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer
Authors
KeywordsFOXA1 mutations
pioneer transcription factor
breast cancer
estrogen receptor
endocrine therapy
Issue Date2020
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/ccell
Citation
Cancer Cell, 2020, v. 38 n. 4, p. 534-550.e9 How to Cite?
AbstractMutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER +) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.
Persistent Identifierhttp://hdl.handle.net/10722/290515
ISSN
2019 Impact Factor: 26.602
2015 SCImago Journal Rankings: 13.922

 

DC FieldValueLanguage
dc.contributor.authorArruabarrena-Aristorena, A-
dc.contributor.authorMaag, JLV-
dc.contributor.authorKittane, S-
dc.contributor.authorCai, Y-
dc.contributor.authorKarthaus, WR-
dc.contributor.authorLadewig, E-
dc.contributor.authorPark, J-
dc.contributor.authorKannan, S-
dc.contributor.authorFerrando, L-
dc.contributor.authorCocco, E-
dc.contributor.authorHO, SY-
dc.contributor.authorTAN, DS-
dc.contributor.authorSallaku, M-
dc.contributor.authorWu, F-
dc.contributor.authorAcevedo, B-
dc.contributor.authorSelenica, P-
dc.contributor.authorRoss, DS-
dc.contributor.authorWitkin, M-
dc.contributor.authorSawyers, CL-
dc.contributor.authorReis-Filho, JS-
dc.contributor.authorVerma, CS-
dc.contributor.authorJauch, R-
dc.contributor.authorKoche, R-
dc.contributor.authorBaselga, J-
dc.contributor.authorRazavi, P-
dc.contributor.authorToska, E-
dc.contributor.authorScaltriti, M-
dc.date.accessioned2020-11-02T05:43:20Z-
dc.date.available2020-11-02T05:43:20Z-
dc.date.issued2020-
dc.identifier.citationCancer Cell, 2020, v. 38 n. 4, p. 534-550.e9-
dc.identifier.issn1535-6108-
dc.identifier.urihttp://hdl.handle.net/10722/290515-
dc.description.abstractMutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER +) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/ccell-
dc.relation.ispartofCancer Cell-
dc.subjectFOXA1 mutations-
dc.subjectpioneer transcription factor-
dc.subjectbreast cancer-
dc.subjectestrogen receptor-
dc.subjectendocrine therapy-
dc.titleFOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer-
dc.typeArticle-
dc.identifier.emailJauch, R: ralf@hku.hk-
dc.identifier.authorityJauch, R=rp02383-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.ccell.2020.08.003-
dc.identifier.pmid32888433-
dc.identifier.scopuseid_2-s2.0-85091237762-
dc.identifier.hkuros318600-
dc.identifier.hkuros315267-
dc.identifier.volume38-
dc.identifier.issue4-
dc.identifier.spage534-
dc.identifier.epage550.e9-
dc.publisher.placeUnited States-

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