Loss of FAT1 drives cyclophosphamide resistance in breast cancer via the Wnt/β-Catenin pathway.

Drug resistance remains a major obstacle to successful chemotherapy, leading to treatment failure and tumor recurrence. Recent studies indicate that mutations in FAT Atypical Cadherin 1 (FAT1) contribute to drug resistance in cancer cells. However, the precise role and underlying mechanisms of FAT1 in breast cancer (BC) remain insufficiently explored. Here, we conducted a comprehensive genomic and transcriptomic analysis, identifying FAT1 as a crucial tumor suppressor gene in BC. Our study demonstrates that genomic alterations in FAT1 are associated with the Wnt/β-catenin pathway activation. We further show that FAT1 loss induces cyclophosphamide (CTX) resistance and leads to the upregulation of the Wnt signaling cascade, accompanied by the accumulation of CTNNB1 transcription factors. Notably, combination therapy effectively alleviates drug resistance by suppressing the Wnt pathway. These findings highlight the critical role of FAT1 loss in mediating CTX resistance in BC and provide insights into potential therapeutic strategies targeting the Wnt pathway.