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.

中文翻译：

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核 PTEN 定位有助于子宫内膜癌中的 DNA 损伤修复，并且可能对该疾病的治疗管理具有诊断益处。

子宫内膜腺癌 (EndoCA) 是美国最常见的妇科癌症类型，其发病率正在增加。大多数患者在手术切除 I 期肿瘤后无病，通常随后进行放疗，但大多数晚期疾病患者复发且预后不良，主要是因为肿瘤对细胞毒性化学疗法无效。PTEN 是 EndoCA 中常见的突变肿瘤抑制因子，以其抑制 AKT/mTOR 信号通路的能力而闻名。PTEN 的核功能也已被提出，但这些功能是否会影响 EndoCA 的发展、进展或结果尚不清楚。使用免疫组织化学，在大约一半的 EndoCA 患者肿瘤中观察到核 PTEN 表达，与分级和细胞质 PTEN 表达无关。在 PTEN 阴性的人类 EndoCA 肿瘤切片、经基因修饰为 PTEN 无效的鼠 EndoCA 组织和 Ishikawa EndoCA 细胞中，通过免疫组织化学和免疫荧光观察到更高水平的 DNA 损伤反应 (DDR) 标记物 γH2AX ，不表达内源性 PTEN。外源性 PTEN-WT 或 PTEN-NLS 的过表达，一种具有附加核定位信号的修饰 PTEN，显着改善了用 DNA 损伤剂处理的 Ishikawa 细胞中的 DDR 和 G2-M 转换。虽然 Olaparib 的 PARP 抑制在表达天然或 PTEN-NLS 的 Ishikawa 细胞中没有那么有效，但 Talazoparib 的抑制不受 PTEN 过表达的影响。这些结果表明，在考虑 DDR 治疗干预时，人类 EndoCA 中的核 PTEN 亚细胞定位可能具有诊断意义。摩尔癌症治疗; 17(9); 1995-2003 年。©2018 AACR。