Abstract Objective: The ubiquitin ligase WWP2 has recently been described to directly interact with PTEN, the major tumor suppressor gene in the PI3K pathway commonly altered in endometrial cancer. Whether alterations of WWP2 contribute to post-translational modifications of the PTEN protein in endometrial cancer are unknown. We sought to determine if WWP2 gene expression levels differ in human endometrial cancer tissues with evidence of post-translational PTEN degradation. We also wished to determine if elevated WWP2 gene expression was associated with clinical prognostic variables. Methods: Twenty-four endometrial cancer specimens collected at hysterectomy were available for analysis. These tumors were stained for PTEN by immunohistochemistry (IHC) and scored using a scale of 0-6. Frozen tissue was then used to determine PTEN and WWP2 expression by Real time PCR (RT PCR). Gene expression was then compared with findings on immunohistochemistry. Patient clinical characteristics including stage, grade, lymph node metastases, recurrence or 2 year disease status were then compared with PTEN and WWP2 expression. Results: Three tumors had elevated PTEN gene expression (at least 2 fold) but low (score of less than 4) PTEN protein on IHC, indicating post-translational modification of PTEN. In these tumors, however, WWP2 expression was not elevated (range 0.004-0.09). There were three tumors with elevation in WWP2 expression (1.9-4.7). PTEN was low in these tumors on IHC, but was also low by RT-PCR indicating genomic, epigenetic or post-transcriptional modification of PTEN. Neither PTEN nor WWP2 expression on RT PCR was associated with stage, grade, lymph node metastases, recurrence or 2 year disease status. Conclusions: In this cohort of tumors, WWP2 did not contribute to post-translational degradation of PTEN. WWP2 expression was not associated with stage, grade, lymph node metastases, recurrence, or 2 year disease status. Citation Format: Aine Clements, Joseph McElroy, Adrian Suarez, Sarmila Majumder, David Cohn, Gustavo Leone. Is the ubiquitin ligase WWP2 playing a role in PTEN degradation in endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1992. doi:10.1158/1538-7445.AM2013-1992