Here, we report, using genetically modified mouse models, that Fbxw7 inhibits esophageal tumorigenesis induced by the carcinogen 4NQO (4-nitroquinoline N-oxide), but not by Pik3Ca<sup>E545K</sup> (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), a frequently mutated gene in human esophageal squamous cell carcinoma (ESCC). Here, PIK3CA is linked to esophageal squamous cell carcinoma.