We demonstrate that concurrent TP53 and oncogenic PIK3CA mutations in the endometrial epithelium led to the development of features of hyperplasia, adenocarcinoma, and endometrial intraepithelial carcinoma in the mouse, and additional ARID1A loss promotes invasive adenocarcinoma with squamous differentiation or metaplasia. The gene discussed is ARID1A; the disease is adenocarcinoma.