Cables role in endometrial differentiation and cancer

描述（由申请人提供）：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暴露于非对抗性雌激素有关。通常可以通过手术治愈。另外，黄体酮是一种天然的子宫内膜细胞增殖抑制剂，已被用于子宫内膜增生或EC，但在关注生育能力的患者中成功率有限。然而，黄体酮的作用机制尚未明确。黄体酮可以影响细胞周期的调节成分（如细胞周期蛋白、细胞周期蛋白依赖性激酶；cdks）。我们最近的研究表明，一种新的细胞周期调节蛋白cable在EC中丢失的频率很高。电缆似乎作为一种连接蛋白，它促进一些cdks的酪氨酸15被非受体酪氨酸激酶磷酸化。Cdk2调节细胞周期的G1 - s期转变，Cdk2酪氨酸磷酸化是抑制性的，导致Cdk2活性降低，减缓细胞生长。电缆增强了这种抑制性磷酸化，因此电缆的损失应导致细胞生长增加，并可能不受控制。黄体酮似乎对来自增殖子宫内膜的上皮细胞的缆索有转录调节作用，但对EC细胞系没有。更有趣的是，缆索缺陷小鼠在3个月大时有子宫内膜增生的迹象，因此似乎是模仿人类疾病的小鼠模型。总的来说，这些数据使我们假设正常子宫内膜上皮中的电缆表达受激素调节，而在转化/转化细胞中电缆缺失或不太有效。此外，我们认为缆索的缺失或水平降低会导致非典型子宫内膜增生和/或肿瘤。为了验证我们的假设，我们提出了以下目标：1)确定孕激素在体外介导电缆诱导的子宫内膜细胞增殖抑制中的作用；2)确定孕激素在子宫内膜细胞中的抗增殖作用是否需要电缆，以及电缆的丢失是否促进了体内EC的发展。3)研究cable缺乏小鼠发情周期中子宫内膜与增殖分化相关的变化及子宫内膜异常生长；4)确定原发性人EC中cable基因失活的机制。本研究将有助于确定缆索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.