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Regulation of Mammary Cell Proliferation by Apical Polarity Proteins

顶端极性蛋白对乳腺细胞增殖的调节

基本信息

批准号：
8846067
负责人：
Clark David Wells
金额：
$ 31.21万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8846067
关键词：
Acinus organ component Adaptor Signaling Protein Address Apical Architecture Binding Biochemical Biological Models Breast Breast Cancer Cell Breast Cancer Model Cancer Etiology Cell Differentiation process Cell Proliferation Cells Cessation of life Controlled Study Data Detection Development Differentiation and Growth Disease-Free Survival Endosomes Epidermal Growth Factor Receptor Epithelial Epithelial Cells Equilibrium Event Fostering Growth Growth Factor Hyperplasia Lead Lesion Longevity MAP2K1 gene MAPK3 gene MCF7 cell MEKs Malignant - descriptor Malignant Neoplasms Mammary gland Maps Mediating Modeling Neoplasm Metastasis Neoplasms Patients Pharmaceutical Preparations Phosphotransferases Premalignant Process Protein Isoforms Proteins RAF1 gene Receptor Protein-Tyrosine Kinases Regulation Relative (related person)Reporting Research Role S-Phase Fraction Shapes Signal Transduction Staging Therapeutic Tissues Woman Xenograft Model base cell growth cellular targeting combat improved malignant breast neoplasm mortality neoplastic novel prevent protective effect scaffold tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is a leading cause of cancer death among women. Current strategies to combat breast cancer mainly target late stage malignancies to extend lifespan; consequently, they often fail to result in disease free survival. While detection of pre-malignant lesions is increasingly accurate, the inability to predict which precancerous lesions lead to neoplastic growth has impeded efforts to identify patients that are likely to develop aggressive neoplasms or drugs to prevent this. This study addresses this issue by defining how the early loss of cellular differentiation is coordinated with the induction of aberrant proliferation by the adaptor protein Amot. Because the breakdown of the apical polarity is one of the earliest essential steps for cells to be sensitized to pro-growth signaling, such studies may explain how highly proliferative breast cancer cells that utilize ErbB type receptor tyrosine kinases for growth are formed. Our model relating these effects to a cellular mechanism posits that polarity proteins induce the prolonged activation of MAPKs. This is consistent with several reports that Ras and Erk1/2 must be targeted to endosomes to undergo prolonged activation that is required for cellular proliferation. The implications of this model for promoting the formation and progression of ErbB2 and triple negative type breast cancers will be investigated.

描述（由申请人提供）：乳腺癌是女性癌症死亡的主要原因。目前防治乳腺癌的策略主要针对晚期恶性肿瘤，以延长寿命；因此，它们往往不能实现无病生存。虽然癌前病变的检测越来越准确，但无法预测哪些癌前病变会导致肿瘤生长，这阻碍了识别可能发展为侵袭性肿瘤的患者或预防这种情况的药物的努力。本研究通过定义细胞分化的早期丧失如何与适配器蛋白Amot诱导的异常增殖相协调来解决这一问题。由于顶端极性的破坏是细胞对促生长信号敏感的最早必要步骤之一，这些研究可能解释了利用ErbB型受体酪氨酸激酶生长的高增殖乳腺癌细胞是如何形成的。我们的模型将这些效应与细胞机制联系起来，假设极性蛋白诱导MAPKs的长时间激活。这与一些报道一致，Ras和Erk1/2必须靶向内体才能经历细胞增殖所需的长时间激活。该模型对促进ErbB2和三阴性型乳腺癌的形成和进展的影响将被研究。