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: 7998161
• 负责人: SENTHIL K MUTHUSWAMY
• 金额: $ 37.77万
• 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/7998161
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Pathologists routinely use changes in cell and tissue structure to understand cancer progression and make assessments for treatment options. However, the molecular pathways that regulate loss of normal cell and tissue structure is poorly studied. The goal of this proposal is to take a new perspective - understand breast cancer initiation and progression as a function of molecular pathways that regulate cell shape. We use three-dimensional organ cultures and mouse models to accomplish this goal. In addition, we collaborate with pathologists to determine the clinical relevance of our findings. This investigation is likely to identify a novel class of biomarkers and drug targets for premalignant and malignant carcinoma.

描述（由申请人提供）：目前乳腺癌的治疗策略主要旨在控制恶性疾病。在大多数情况下，这些策略可以延长患者的寿命，但很少能成功阻止癌症。我相信，通过了解癌前病变发展和恶性癌症进展所涉及的分子机制，我们将能够制定早期治疗乳腺癌的策略，从而有更大的治愈机会。所有浸润性乳腺癌均起源于上皮细胞，在正常乳房中，上皮细胞在导管和小叶内排列有明显的极化组织。细胞极性和组织的变化是病理学家对癌症进行分级的关键标准，支持细胞极性和组织组织的调节是癌症进展的关键组成部分的观点。然而，人们对调节细胞极性变化的分子机制知之甚少。我相信，癌症中极性途径改变的机制代表了癌细胞生物学中一个尚未开发的领域，它为发现早期诊断和治疗的新策略以有效根除浸润性乳腺癌提供了巨大的潜力。在过去的资助期间，我们发现 ErbB2 直接与 Par6/aPKC 极性复合物相互作用。该途径对于 ErbB2 破坏细胞极性和抑制细胞死亡的能力是必需的，但对于诱导细胞增殖来说是可有可无的。这些结果确定了极性通路在 ErbB2 阳性乳腺癌中的两个主要作用 - 1）破坏细胞和组织结构； 2）抑制细胞死亡。后者是一个意外的发现，之前在果蝇和蠕虫中进行的所有研究都没有预测到这一点。在本提案中，我们建议扩展这些发现，更深入地了解 ErbB2 与极性蛋白相互作用的机制，并确定 ErbB2-Par6 极性复合物下游调节细胞死亡的途径。在这些研究的过程中，我们将开发强大的体内模型，这不仅使我们能够确定我们的发现的体内相关性，而且还可以作为临床前研究的工具。除此之外，我们还建议扩大范围并研究极性途径的改变如何促进侵袭性进展和转移。因此，我相信我们的提案采取了创新策略，并探索了癌症生物学中未经探索的领域，其目标是寻找一类新的生物标志物和药物靶点。 公共卫生相关性：病理学家通常利用细胞和组织结构的变化来了解癌症进展并对治疗方案进行评估。然而，调节正常细胞和组织结构损失的分子途径却很少被研究。该提案的目标是采取新的视角——将乳腺癌的发生和进展理解为调节细胞形状的分子途径的函数。我们使用三维器官培养和小鼠模型来实现这一目标。此外，我们与病理学家合作以确定我们研究结果的临床相关性。这项研究可能会发现一类新型的癌前癌和恶性肿瘤的生物标志物和药物靶点。