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.
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•FOXA1 mutations are enriched in metastatic tumors•FOXA1 mutations are associated with worse outcome to aromatase inhibitors•Wing2 mutations promote an enhanced estrogen response upon estrogen•SY242CS induces alternative chromatin states by binding to a non-canonical motif
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.
