乳腺癌研究：桥粒结合蛋白质Prep或可成为乳腺癌治疗新靶点

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乳腺癌研究：桥粒结合蛋白质Prep或可成为乳腺癌治疗新靶点
2012-04-23
对乳腺癌的早期检测和治疗能提高患者生存机会，同时在对抗疾病的战役中我们仍然需要新的治疗方法。BioMed中心开放存取期刊《乳腺癌研究》公布的新研究显示，与桥粒（将细胞粘贴在一起的胶）结合的蛋白质Prep能够抑制乳腺癌，这种蛋白质为未来的治疗提供一种有潜力的新靶点。

桥粒将相邻的细胞连接在一起，它是蛋白质的微聚体，主要功能是维持体内器官组织机械强度。桥粒在抑制癌症过程中也发挥了辅助作用。斯坦福大学、加州大学伯克利分校、加州大学戴维斯分校的研究者发现在乳腺上皮细胞中Prep蛋白质是和桥粒结合的。

研究领导者LauraAttardi博士描述了小鼠丢失Prep是怎样影响正常乳腺的组织功能。她说：“Prep缺失导致乳腺上皮细胞桥粒蛋白表达缺陷，同时乳腺组织中有增强的炎症反应，肿瘤发展的速度更快。我们也发现在实验室中乳腺癌细胞有反常的低水平Prep。”

这个结果显示Prep是将细胞紧密连接的细胞胶的组成部分。Prep在预防乳腺癌中发挥双重作用。炎症细胞促进癌症，缺少细胞粘附是癌症转移过程中的一个条件。Prep可能是检测乳腺癌的一个新标记物，也可能是分子治疗的一个新靶点。

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Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.
Breast Cancer Res 2012 Apr;142:R65

Dusek RL Bascom JL Vogel H Baron S Borowsky AD Bissell MJ Attardi LD

Abstract
ABSTRACT: INTRODUCTION: Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with severe blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, Perp's role in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp's function in the mammary gland. METHODS: Western blot and immunofluorescence analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared to those in untransformed cells by Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed and tumor-free survival was assessed using Kaplan Meier analysis. RESULTS: We show that Perp protein is expressed in the mammary epithelium, where it co-localizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared to untransformed cells. Importantly, Perp-deficiency also promotes the development of mouse mammary cancer. CONCLUSIONS: Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.