Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgr^cre/+Erbb2^f/fPten^f/f (Erbb2^d/d Pten^d/d) was developed to evaluate the effect of ERBB2 targeted therapy in endometrial cancer with PTEN deficiency. Histopathological and molecular analysis was performed for Pten^d/d and Erbb2^d/dPten^d/d mice. Histopathological analysis revealed that Erbb2^d/dPten^d/d mice significantly reduced development and progression of endometrial cancer compared to Pten^d/d mice. Furthermore, percentage of proliferative cells in Erbb2^d/dPten^d/d mice revealed anti-tumorigenic effect of Erbb2 ablation compared to Pten^d/d mice. Our results demonstrate that Erbb2 ablation reveals a significant suppression of tumorigenesis on endometrial cancer of Pten^d/d mice. Our results suggest that Erbb2 functions as an oncogene in endometrial cancer of Pten^d/d mice implying that Erbb2 targeting can be used as an effective therapeutic approach for treatment of endometrial cancer with PTEN deficiency to hinder cancer development.