Cables role in endometrial differentiation and cancer

描述（申请人提供）：子宫内膜癌（EC）是美国最常见的妇科恶性肿瘤，在大多数情况下被认为与过度使用非对抗性雌激素有关。EC通常可以通过手术治愈。或者，孕酮，一种子宫内膜细胞增殖的天然抑制剂，已被用于子宫内膜增生或EC患者谁是关注生育能力的有限成功。然而，孕酮的作用机制尚未确定。孕酮可以影响细胞周期的调节组分（例如细胞周期蛋白、细胞周期蛋白依赖性激酶; cdk）。我们最近的研究表明，电缆，一个新的细胞周期调控蛋白，在EC中以高频率丢失。电缆似乎作为一个连接蛋白，这有利于酪氨酸15磷酸化的一些cdk的非受体酪氨酸激酶。Cdk 2调节细胞周期的G1 S-期转变，并且cdk 2酪氨酸磷酸化是抑制性的，并导致cdk 2活性降低和减缓细胞生长。电缆增强这种抑制性磷酸化，因此电缆的损失应导致增加，并可能不受控制的细胞生长。孕激素似乎转录调节电缆在上皮细胞来源于增殖的子宫内膜，但不是在EC细胞系。更有趣的是，Cables缺陷小鼠在3个月大时有子宫内膜增生的证据，因此似乎是模拟人类疾病的小鼠模型。总的来说，这些数据使我们假设Cables在正常子宫内膜上皮中的表达是受子宫内膜调节的，而Cables在转化/转化细胞中不存在或无效。此外，我们认为Cables的丢失或水平降低会导致非典型子宫内膜增生和/或瘤形成。为了检验我们的假设，我们提出了以下目标：1）确定孕酮在体外介导Cables诱导的子宫内膜细胞增殖抑制中的作用，2）确定Cables是否是孕酮在子宫内膜细胞中的抗增殖作用所必需的，以及Cables的丢失是否促进体内EC的发展，3）研究Cables缺陷小鼠在动情周期中与增殖和分化相关的子宫内膜变化以及异常子宫内膜生长，4）确定Cables基因在原代人EC中失活的机制。这项研究将有助于确定电缆在正常和恶性子宫内膜上皮中的作用。

DESCRIPTION (provided by applicant): Endometrial cancer (EC) is the most common gynecologic malignancy in the United States and is believed in most cases to be related to overexposure to unopposed estrogens. EC is usually curable with surgery. Alternatively, progesterone, a natural inhibitor of cellular proliferation of the endometrium, has been used with limited success for endometrial hyperplasia or EC in patients who are concerned about fertility. The mechanisms of progesterone action, however, have yet to be defined. Progesterone can influence regulatory components of the cell cycle (e.g. cyclins, cyclin dependent kinases; cdks). Our recent studies have demonstrated that Cables, a novel cell cycle regulatory protein, is lost at a high frequency in EC. Cables appears to act as a linker protein, which facilitates tyrosine 15 phosphorytation of some cdks by non-receptor tyrosine kinases. Cdk2 regulates the G1 S-phase transition of the cell cycle and cdk2 tyrosine phosphorylation is inhibitory and leads to decreased cdk2 activity and slows cell growth. Cables enhances this inhibitory phosphorylation, so loss of Cables should result in increased, and possibly uncontrolled, cell growth. Progesterone appears to transcriptionally regulate Cables in epithelial cells derived from proliferating endometrium, but not in EC cell lines. More interesting, the Cables deficient mice have evidence of endometrial hyperplasia at 3 months of age and as such appears to be a mouse model that mimics the human disease. Collectively, these data have led us to hypothesize that Cables expression in normal endometrial epithelium is hormonally regulated, and Cables is absent or tess effective in transformed/transforming cells. Furthermore, we believe that a loss, or a reduced level of, Cables leads to atypical endometrial hyperptasia and/or neoplasia. To test our hypotheses, we have proposed the following aims 1) Determine the role of progesterone in mediating Cables induced inhibition of endometrial cell proliferation in vitro, 2) Determine if Cables is required for the anti-proliferative effects of progesterone in endometrial cells, and if loss of Cables facilitates EC development in vivo, 3) Investigate the endometrial changes associated with proliferation and differentiation during the estrous cycle and abnormal endometrial growth in Cables deficient mice, 4) Determine the mechanism of Cables gene inactivation in primary :human EC. The studies in this proposal will help determine the: role of Cables in I normal and malignant endometrial epithelium.