Overexpression of enhancer of zeste homolog 2 (EZH2) and focal adhesion kinase (FAK) in high grade endometrial carcinoma

ObjectiveThe deregulation of E-cadherin is associated with Src/FAK signaling axis and histone deacetylase (HDAC)/EZH2 activity. However, the association between EZH2 and FAK and its clinical significance in endometrial carcinoma has not been reported.Methods202 archived cases of endometrial carcinoma (1996–2000) were reviewed and divided into two subtypes. TMAs were developed as per established procedures. EZH2, FAK, and pFAK immunohistochemical stains were performed and the expression was scored as negative (0), low (1) and high (2). Proper statistical analysis was used to assess the correlation between the expression profiles and the clinicopathological parameters and clinical outcome.ResultsA total of 141 (69.8%) type-1 tumors and 61 (30.2%) type-2 tumors were identified. EZH2 overexpression was identified in 7.6% of type-1 tumors vs. 63% of type-2 tumors (p < 0.001). FAK and pFAK overexpression was only seen in 24.8% and 1.7% of Type-1 tumors as compared to 72% and 58.8% of type-2 tumors, respectively (p < 0.001). A positive correlation between the expression of EZH2, FAK, pFAK and PTEN (p < 0.0001) was found. The overexpression of EZH2, FAK, and pFAK were significantly associated with high histologic grade, angiolymphatic invasion, lymph node metastasis, myometrial invasion and cervical involvement (p < 0.01). Kaplan–Meier analysis demonstrates that the overexpression of EZH2 (p = 0.0024), FAK and pFAK (p = 0.0001) was significantly associated with decreased overall survival.ConclusionThe overexpression of EZH2, FAK and pFAK correlates with well established pathologic risk factors and may predict a more aggressive biologic behavior in endometrial carcinoma, transforming these proteins into potential therapeutic targets for treatment of endometrial cancer.

► Upregulation of EZH2 and FAK is significantly associated with high histologic grade.
► Upregulation of EZH2 and FAK is significantly associated with other high risk pathologic factors.
► Upregulation of EZH2 and FAK is significantly associated with decreased overall survival.