FAT1, encoding a protocadherin, is one of the most frequently mutated genes in human cancers. It activates multiple signaling pathways like Wnt/β -catenin, Hippo, and MAPK/ERK, influencing cell proliferation, migration, and invasion. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions [2].

In mouse models of skin squamous cell carcinoma and lung tumours, Fat1 deletion accelerates tumour initiation and malignant progression, promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype, increases tumour stemness, and leads to spontaneous metastasis. Mechanistically, FAT1 loss of function activates a CAMK2-CD44-SRC axis promoting YAP1 nuclear translocation and ZEB1 expression for the mesenchymal state, and inactivates EZH2 to promote SOX2 expression for the epithelial state [1]. In ER + breast cancer, FAT1 loss-of-function mutations are linked to resistance to CDK4/6 inhibitors, as FAT1 loss elevates CDK6 through the Hippo pathway [3].

In conclusion, Fat1 is crucial in maintaining organ development and its abnormal expression is associated with tumorigenesis. Studies using Fat1 KO/CKO mouse models have revealed its roles in cancer initiation, progression, and drug resistance, providing insights into potential cancer therapies.