Proteolytic processing of cyclin E in breast cancer

在许多乳腺癌中，全长细胞周期蛋白E通过弹性蛋白酶介导的翻译后修饰 氨基末端两个特定位点的蛋白水解性裂解，导致低分子的产生 重量(LMW)亚型在细胞周期中具有更高的活性和对细胞周期蛋白依赖性激酶的抗性 抑制剂。低分子形式的细胞周期蛋白E是重要的，因为它们作为预后标志物的重要作用。 乳腺癌患者及其对细胞周期通路的参与。我们之前的研究表明， 在25-35%的乳腺癌和乳腺癌患者中观察到低分子形式的细胞周期蛋白E的表达 这种表达与不良的临床结果有很强的相关性。此外，我们已经报道了 低分子形式的细胞周期蛋白E在功能上高度活跃，并能抵抗p21和p27的抑制。最近我们 开发出在乳腺中过度表达低分子形式细胞周期蛋白E的转基因小鼠。这些老鼠 发展成具有转移潜能的肿瘤。这项研究的核心假设是， 与乳房直接相关的是低分子形式的细胞周期蛋白E，而不是全长的细胞周期蛋白E 癌症的进展和转移，使乳腺上皮更容易发生肿瘤。调查 本提案中概述的内容将提供有关LMW自行车形成的机制的详细信息 E介导它们在乳腺肿瘤发生中的作用。具体地说，我们将：1)确定致癌因素 全长细胞周期蛋白E的潜能及其弹性酶裂解在低分子量细胞周期蛋白E诱导的乳腺中的作用 肿瘤。2)确定全长和低分子形式的细胞周期蛋白E之间的生化差异。 探讨CDK2在LMW-Cyclin E过表达介导的乳腺肿瘤形成中的作用 4)确定肿瘤维持和复发所需的细胞周期蛋白E。 这项拟议的研究具有创新性，因为它不仅研究了低分子形式的细胞周期蛋白E 乳腺上皮易癌，也是细胞周期蛋白E相关的机制 下游的改变会导致体内肿瘤的形成。总体而言，通过 建议的研究可能对早期和晚期乳房的妇女具有巨大的临床意义。 癌症。我们已经知道细胞周期蛋白E的过度表达与不良的患者预后相关；如果细胞周期蛋白E 过度表达也使乳腺易于遗传不稳定，从而导致肿瘤的发生。 提示低分子形式的细胞周期蛋白E在乳腺癌中的表达具有致病作用。

In many breast cancers, full length cyclin E is post-translationally modified through elastase mediated proteolytic cleavage of two specific sites in the amino terminus, resulting in the generation of low molecular weight (LMW) isoforms that have increased activity in cell cycle and resistance to cyclin-dependent kinase inhibitors. The LMW forms of cyclin E are important because of their significant role as prognostic markers in breast cancer patients and their involvement in cell cycle pathways. Our previous studies have shown that the expression of the LMW forms of cyclin E is observed in 25-35% of patients affected with breast cancer and such expression correlates very strongly with poor clinical outcome. Additionally, we have reported that the LMW forms of cyclin E are functionally hyperactive and resistant to inhibition by p21 and p27. Recently we developed transgenic mice overexpressing the LMW forms of cyclin E in the mammary gland. These mice develop tumors with metastatic potential. Thecentral hypothesis of theproposed research, is that the overexpression of the LMWforms of cyclin E, and not thefull-length cyclin E, are directly related to breast cancer progression and metastasis, predisposing the mammary epithelium to oncogenesis. The investigations outlined in this proposal will provide details regarding the mechanism through which the LMW forms of cyclin E mediate their effects in mammary gland tumorigenesis. Specifically,we will: 1) Determine the oncogenic potential of full length cyclin E and the role of elastase cleavage in mediating LMW cyclin E-induced mammary tumors. 2) Identify the biochemical differences between the full length and LMW forms of cyclin E. 3) Investigate the role of CDK2 in breast tumor formation mediated by LMW cyclin E overexpression in the mammary gland, and lastly 4) determine the requirement of cyclin E for tumor maintenance and recurrence. The proposed research is innovative because it investigates not only whether the LMW forms of cyclin E predispose mammary epithelium to oncogenesis, but also the mechanism by which cyclin E-associated downstream alterations lead to tumor formation in vivo. Collectively, the information gained through the proposed studies could have tremendous clinical relevance for women with early stage and advanced breast cancer. We already know that cyclin E overexpression correlates with poor patient outcome; if cyclin E overexpression also predisposes the mammary gland to genetic instability leading to tumorigenesis it would suggest a causative function for the expression of the LMW forms of cyclin E in breast cancer.