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。当前打击乳腺癌的策略主要针对后期恶性肿瘤，以延长寿命；因此，它们通常无法导致无疾病生存。虽然检测到恶性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侵袭性肿瘤或药物以防止这种情况的患者的努力。这项研究通过定义了如何与衔接蛋白AMOT诱导异常增殖相协调的细胞分化的早期损失来解决这一问题。由于根尖极性的分解是将细胞敏感到促增长信号传导的最早的基本步骤之一，因此此类研究可能解释了如何形成高度增殖性的乳腺癌细胞，这些乳腺癌细胞是如何形成生长的。我们将这些作用与细胞机制相关的模型认为，极性蛋白会诱导MAPK的延长激活。这与几个报道一致，即Ras和Erk1/2必须针对内体，以进行延长细胞增殖所需的激活。将研究该模型对促进ERBB2和三重阴性乳腺癌的形成和进展的含义。