Endometrial
adenocarcinoma (EndoCA) is the most common gynecologic
cancer type in the United States, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I
tumors, which is often followed by
radiotherapy, but most patients with advanced disease recur and have a poor prognosis, largely because the
tumors become refractory to cytotoxic
chemotherapies. PTEN, a commonly mutated
tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient
tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, γH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA
tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Overexpression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added
nuclear localization signal, significantly improved both DDR and G2-M transition in Ishikawa cells treated with
a DNA-damaging agent. Whereas PARP inhibition with
Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with
Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention. Mol
Cancer Ther; 17(9); 1995-2003. ©2018 AACR.