Cell polarity pathways and ErbB2 mediated tumorigenesis

细胞极性途径和 ErbB2 介导的肿瘤发生

• 批准号: 8205028
• 负责人: SENTHIL K MUTHUSWAMY
• 金额: $ 40.59万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205028
• 关键词: Address; Affect; Antineoplastic Agents; Apoptosis; Architecture; Area; Belief; Biological Markers; Breast; Cancer Biology; Carcinoma; Cell Death; Cell Polarity; Cell Proliferation; Cell Shape; Cells; Cellular biology; Complex; Development; Disease; Drosophila genus; Drug Delivery Systems; Drug resistance; Duct (organ) structure; Early Diagnosis; Early treatment; Epithelial; Epithelial Cells; Funding; Genes; Goals; Investigation; Lesion; Lobule; Longevity; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Mutation; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oncogenes; Oncogenic; Organ Culture Techniques; Pathologist; Pathway interactions; Patients; Play; Premalignant; Process; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Reporter; Role; Signal Transduction; Stimulation of Cell Proliferation; Structure; Therapeutic; Tissues; cancer cell; cancer initiation; cell motility; clinically relevant; in vivo; in vivo Model; innovation; malignant breast neoplasm; mouse model; novel; novel strategies; preclinical study; tool; tumor progression; tumorigenesis

Current therapeutic strategies for breast cancer are mostly aimed at controlling malignant disease. In most cases, these strategies extend a patient's lifespan, but are rarely successful in stopping the cancer. I believe that by gaining an understanding of the molecular mechanisms involved in development of premalignant lesions and progression to malignant cancer, we will be able to devise strategies to treat breast cancer early when there is a greater chance for cure. All invasive breast cancers originate from epithelial cells, which in the normal breast are arranged with a distinct polarized organization within ducts and lobules. Changes in cell polarity and organization are a key criterion used by pathologists in grading cancers, supporting the notion that regulation of cell polarity and tissue organization is a critical component of cancer progression. However, very little is known about the molecular mechanisms that regulate changes in cell polarity. It is my belief that mechanisms by which polarity pathways are altered in cancer represent an untapped area of cancer cell biology that offers tremendous potential for discovery of novel strategies for early diagnosis and treatment to effectively eradicate invasive breast cancer. During the past funding period we discovered that ErbB2 directly interacts with the Par6/aPKC polarity complex. This pathway was required for the ability of ErbB2 to disrupt cell polarity and inhibit cell death, but was dispensable to induce cell proliferation. These results have identified two major roles for polarity pathways in ErbB2 positive breast cancers - 1) to disrupt cell and tissue architecture; 2) to inhibit cell death. The latter was an unexpected finding, which was not predicted by all the studies previously performed in Drosophila and Worms. In this proposal we propose to extend on these finding and develop a deeper understanding of the mechanisms by which ErbB2 interacts with the polarity protein and identify the pathways downstream of ErbB2-Par6 polarity complex that regulates cell death. In the process of these studies we will develop robust in vivo models that will not only allow us to determine the in vivo relevance of our finding but will also function as tools for preclinical studies. In addition to the above, we also propose extend the scope and investigate how alterations in polarity pathways promote invasive progression and metastasis. Thus, I believe that our proposal takes an innovative strategy and exploits an unexplored area of cancer biology with the goal of finding a new class of biomarkers and drug targets.

当前的乳腺癌治疗策略主要旨在控制恶性疾病。 在大多数情况下，这些策略延长了患者的寿命，但很少成功地阻止癌症。 我认为，通过了解参与发展的分子机制 前病变和对恶性癌的发展，我们将能够制定策略来治疗 乳腺癌很早就可以治愈。所有浸润性乳腺癌均来自 上皮细胞在正常乳房中与管道内的极化组织排列 和小叶。细胞极性和组织的变化是病理学家在评分时使用的关键标准 癌症，支持细胞极性和组织组织调节是关键组成部分的观念 癌症进展。但是，关于调节变化的分子机制知之甚少 在细胞极性中。我相信，癌症中极性途径改变的机制代表 癌细胞生物学未开发的领域，为发现新型策略的巨大潜力 早期诊断和治疗可有效消除侵入性乳腺癌。 在过去的资金期间，我们发现ERBB2直接与PAR6/APKC相互作用 极性复合物。 ERBB2破坏细胞极性并抑制细胞的能力需要此途径 死亡，但可以诱导细胞增殖。这些结果已经确定了两个主要角色 ERBB2阳性乳腺癌中的极性途径-1）破坏细胞和组织结构； 2）抑制 细胞死亡。后者是一个出乎意料的发现，以前所有研究都没有预测 在果蝇和蠕虫中进行。 在此提案中，我们建议扩展这些发现并对 ERBB2与极性蛋白相互作用并确定下游途径的机制 调节细胞死亡的ERBB2-PAR6极性复合物。在这些研究的过程中，我们将开发 强大的体内模型，不仅可以使我们确定我们发现的体内相关性，而且还将 充当临床前研究的工具。除上述内容外，我们还建议扩展范围，并 研究极性途径的变化如何促进侵入性进程和转移。因此，我 相信我们的建议采用创新策略，并利用未开发的癌症生物学领域 目的是寻找新的生物标志物和药物靶标。