FOXA1 mutations reveal distinct chromatin profiles and influence therapeutic response in breast cancer Journal Article

Authors: Arruabarrena-Aristorena, A.; Maag, J. L. V.; Kittane, S.; Cai, Y.; Karthaus, W. R.; Ladewig, E.; Park, J.; Kannan, S.; Ferrando, L.; Cocco, E.; Ho, S. Y.; Tan, D. S.; Sallaku, M.; Wu, F.; Acevedo, B.; Selenica, P.; Ross, D. S.; Witkin, M.; Sawyers, C. L.; Reis-Filho, J. S.; Verma, C. S.; Jauch, R.; Koche, R.; Baselga, J.; Razavi, P.; Toska, E.; Scaltriti, M.
Article Title: FOXA1 mutations reveal distinct chromatin profiles and influence therapeutic response in breast cancer
Abstract: Mutations 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. © 2020 Elsevier Inc. Arruabarrena-Aristorena et al. determine that mutations in the pioneer transcription factor FOXA1 lower the therapeutic response to aromatase inhibitors in ER+ breast cancer. Mechanistically, two phenotypic groups are established: hypermorphic Wing2 mutants that augment estrogen response, and a neomorphic SY242CS mutant that promotes an alternative pioneering, and cistromic and transcriptomic function. © 2020 Elsevier Inc.
Keywords: breast cancer; transcriptomics; transcription; estrogen receptor; endocrine therapy; epigenomics; chromatin accessibility; esr1 mutations; pioneer transcription factor; foxa1 mutations
Journal Title: Cancer Cell
Volume: 38
Issue: 4
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2020-10-12
Start Page: 534
End Page: 550.e9
Language: English
DOI: 10.1016/j.ccell.2020.08.003
PUBMED: 32888433
PROVIDER: scopus
Notes: Article -- Export Date: 2 November 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Charles L Sawyers
    199 Sawyers
  2. Dara Stacy Ross
    87 Ross
  3. Erik Manfred Ladewig
    14 Ladewig
  4. Jorge Sergio Reis
    476 Reis
  5. Jose T Baselga
    483 Baselga
  6. Maurizio Scaltriti
    161 Scaltriti
  7. Richard Patrick Koche
    98 Koche
  8. Pedram Razavi
    106 Razavi
  9. Eneda   Toska
    30 Toska
  10. Matthew David Witkin
    14 Witkin
  11. Emiliano Cocco
    28 Cocco
  12. Yanyan Cai
    12 Cai
  13. Jesper Lars Viktor Maag
    10 Maaaag
  14. Jane Park
    7 Park
  15. Fan Wu
    6 Wu