Journal
CANCER CELL
Volume 38, Issue 4, Pages 534-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.08.003
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Funding
- NIH [P30 CA008748, RO1CA19064201A1]
- Breast Cancer Research Foundation
- Geoffrey Beene Cancer Research Center
- Stand Up To Cancer
- V Foundation
- National Science Foundation
- NSFC of Hong Kong/China [31771454]
- RGC/GRF of Hong Kong/China [17128918]
- HMRF of Hong Kong/China [06174006]
- Education Department of the Basque Country Government in Spain
- Prostate Cancer Foundation
- MSK Society
- [NCI K00CA212478]
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Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER+) breast cancers. Examining FOXA1 in similar to 5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third beta 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.
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