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

• 批准号: 8108546
• 负责人: Clark David Wells
• 金额: $ 31.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108546
• 关键词: Acinus organ component; Adaptor Signaling Protein; Address; Apical; Architecture; Binding; Biochemical; Biological Models; Breast; Breast Cancer Cell; 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 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; U-0126; Woman; Xenograft Model; base; cell growth; cellular targeting; combat; improved; malignant breast neoplasm; mortality; neoplastic; novel; prevent; protective effect; scaffold; tumor; tumor progression

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. PUBLIC HEALTH RELEVANCE: A majority of the 40,000 mortalities from breast cancer each year follow therapeutic strategies that target late stage malignant tumors. The premise of this proposal is that long-term survival could be substantially improved if early hyperplastic lesions were prevented from developing into aggressive cancers; a process that is mainly characterized by the loss of epithelial architecture and aberrant cellular accumulation. To this end, this study will investigate a novel mechanism whereby loss of cellular shape directly regulates cell growth to promote early initiation of cellular proliferation and invasiveness.

描述(申请人提供)：乳腺癌是女性癌症死亡的主要原因。目前抗击乳腺癌的策略主要针对晚期恶性肿瘤以延长生命；因此，它们往往无法导致无病生存。虽然对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，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。这项研究通过定义早期细胞分化的丧失如何与接头蛋白AMOT诱导异常增殖相协调来解决这个问题。因为顶极的破坏是细胞对促生长信号敏感的最早的必要步骤之一，这样的研究可以解释利用ErbB型受体酪氨酸激酶进行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一种细胞机制联系起来，假设极性蛋白诱导MAPK的长时间激活。这与一些报道一致，即RAS和ERK1/2必须针对内小体，才能经历细胞增殖所需的长期激活。这一模型对于促进ErbB2和三阴性乳腺癌的形成和发展的意义将被研究。 公共卫生相关性：每年死于乳腺癌的40,000人中的大多数遵循针对晚期恶性肿瘤的治疗策略。这一建议的前提是，如果早期增生性病变不发展为侵袭性癌症，长期存活率可能会大幅提高；这一过程的主要特征是上皮结构的丧失和细胞的异常堆积。为此，本研究将探索一种新的机制，即细胞形状的丧失直接调节细胞的生长，以促进细胞增殖和侵袭的早期启动。