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.

先驱转录因子FOXA1中的突变是雌激素受体阳性（ER ⁺）乳腺癌的标志。在约5,000名乳腺癌患者中检查FOXA1可以确定Wing2区的几个热点突变以及位于第三条β链的乳腺癌特异性突变SY242CS。使用临床基因组策划的队列以及乳腺癌模型，我们发现FOXA1突变与对芳香化酶抑制剂的较低反应有关。从机制上讲，Wing2突变在雌激素刺激下显示出在ER位点的染色质结合增加，并且增强了ER介导的转录，而染色质可及性没有变化。相比之下，SY242CS具有新形态特性，包括能够打开不同的染色质区域并激​​活备选的犯罪现场和转录组。结构建模预测SY242CS赋予构象改变，该构象改变介导与非经典DNA图案的稳定结合。综上所述，我们的结果提供了有关FOXA1突变如何扰乱其决定癌症进展和治疗反应的功能的见解。