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都起源于腺体结构内的上皮细胞。普通的 上皮结构/极性对于维持细胞与其细胞之间的微妙平衡至关重要 微环境；这种平衡的破坏可能导致在过程中观察到的异常细胞行为 癌症的发生和进展。事实上，病理学家经常利用细胞和组织的变化 了解癌症进展并评估治疗方案的架构。尽管 了解细胞结构的重要性，细胞和组织结构的机制 癌症中的破坏仍然知之甚少。了解分子机制可能 通过癌症中细胞、组织和结构的失调，不仅可以让我们有更好的了解 了解肿瘤微环境的变化，同时还确定一类新的生物标志物和药物 目标。 在过去的资助期间，我们发现癌基因与极性调节剂相互作用 破坏细胞极性和上皮结构的三维组织。互动是 与癌基因诱导细胞增殖的能力无关。令人惊讶的是，癌基因极性 基因相互作用是保护细胞免于凋亡所必需的。因此，极性基因发挥着重要作用 在癌症中。它们是癌基因诱导细胞和组织结构变化所必需的 保护细胞免于死亡。我认为我们才刚刚开始摸索，还有很多事情有待理解 极性途径在启动和发生过程中与癌基因合作的分子机制 癌症的进展。 在本提案中，我们以上一个资助期的结果为基础来解决以下问题：1) 更深入地了解 ErbB2 与极性通路相互作用的机制； (2) 确定极性途径如何保护细胞免于凋亡以及它在细胞凋亡过程中发挥什么作用 (3)确定极性途径如何与ErbB2配合促进耐药性的发展 上皮间质转化和恶性进展。 因此，该提案的目标是采取新的视角——了解癌症的发生和发展 作为细胞极性途径失调的函数的进展。