Mechanisms by which Polarity Proteins Regulate Initiation and Progression of Brea

极性蛋白调节 Brea 起始和进展的机制

• 批准号: 7668146
• 负责人: SENTHIL K MUTHUSWAMY
• 金额: $ 24万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668146
• 关键词: Address; Affect; Antineoplastic Agents; Apoptosis; Architecture; Biological Markers; Breast; Carcinoma; Cell Death; Cell Polarity; Cell Proliferation; Cell Shape; Cells; Class; Complex; Depth; Development; Disease; Disruption; Drug Delivery Systems; Drug resistance; Epithelial; Epithelial Cells; Equilibrium; Funding; Genes; Goals; Ice; MLLT4 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Molecular; Mutation; Normal Cell; Normal tissue morphology; Numbers; Oncogenes; Oncogenic; Pathologist; Pathway interactions; Play; Premalignant; Proteins; Receptor Protein-Tyrosine Kinases; Role; Role playing therapy; Signal Transduction; Stimulation of Cell Proliferation; Structure; Thinking; Tissues; cell behavior; cell motility; epithelial to mesenchymal transition; gene interaction; in vivo; malignant breast neoplasm; novel; tumor; tumor progression; tumorigenesis

Almost all malignant breast cancers originate from epithelial cells within glandular structures. Normal epithelial architecture/polarity is critical to maintain the delicate balance between a cell and its microenvironment; disruption of this balance can result in the aberrant cell behavior observed during initiation and progression of carcinoma. In fact, pathologists routinely use changes in cell and tissue architecture to understand cancer progression and make assessments for treatment options. Despite the appreciation of the importance of cell architecture, the mechanism by which cell and tissue architecture is disrupted in carcinoma remains poorly understood. It is likely that understanding the molecular mechanisms by which cell and tissue and architecture is deregulated in carcinoma will not only allow us to have a better understanding of changes in tumor microenvironment but also identify a new class of biomarkers and drug targets. During the past funding period we discovered that oncogenes interact with polarity regulators to disrupt cell polarity and three-dimensional organization of epithelial structures. The interaction was independent of the ability of oncogenes to induce cell proliferation. Surprisingly, the oncogene-polarity genes interaction was required for protecting cells from apoptosis. Thus, polarity genes play important roles in carcinoma. They are required for oncogenes to induce changes in cell and tissue architecture and for protecting cells from death. I think we have just begun to scrape the ice, much remains to be understood on the molecular mechanisms by which polarity pathways cooperate with oncogenes during initiation and progression of carcinoma. In this proposal we build on our results from the previous funding period to address the following: 1) Develop a deeper understanding of the mechanism by which ErbB2 interacts with polarity pathways; (2) Determine how polarity pathways protects cells from apoptosis and what roles does this play during development of drug resistance (3) Determine how polarity pathways cooperate with ErbB2 to promote epithelial to mesenchymal transition and malignant progression. Thus the goal of this proposal is to take a new perspective - understand carcinoma initiation and progression as a function of deregulated cell polarity pathways.

几乎所有恶性乳腺癌源自腺体结构内的上皮细胞。普通的 上皮结构/极性对于维持细胞及其之间的微妙平衡至关重要 微环境；这种平衡的破坏会导致在 癌的启动和进展。实际上，病理学家通常在细胞和组织中使用变化 了解癌症进展并评估治疗方案的建筑。尽管有 欣赏细胞结构的重要性，细胞和组织结构的机制 癌症中断仍然知之甚少。理解分子机制很可能 细胞，组织和建筑在癌中的管制不仅可以使我们变得更好 了解肿瘤微环境的变化，但也确定了一类新的生物标志物和药物 目标。 在过去的资金期间，我们发现Oncogenes与极性调节器相互作用 破坏细胞极性和上皮结构的三维组织。相互作用是 独立于癌基因诱导细胞增殖的能力。令人惊讶的是，致癌基因 保护细胞免受细胞凋亡的影响需要基因相互作用。因此，极性基因起着重要作用 在癌中。它们是癌基因诱导细胞和组织结构的变化所必需的 保护细胞免受死亡。我认为我们刚刚开始刮擦冰，还有很多待了解 极性途径在开始期间与癌基因合作的分子机制和 癌的进展。 在此提案中，我们基于以下资金期的结果，以解决以下内容：1） 对ERBB2与极性途径相互作用的机制有了更深入的了解。 （2） 确定极性途径如何保护细胞免受凋亡的侵蚀以及在此期间起什么作用 耐药性的发展（3）决定了极性途径如何与ERBB2合作以促进 上皮到间充质转变和恶性进展。 因此，该提案的目的是采用新的观点 - 了解癌的启动和 进展是失控的细胞极性途径的函数。