Cell polarity pathways and ErbB2 mediated tumorigenesis

描述（申请人提供）：目前乳腺癌的治疗策略主要是为了控制恶性疾病。在大多数情况下，这些策略延长了患者的寿命，但很少能成功地阻止癌症。我相信，通过了解癌前病变发展到恶性癌症的分子机制，我们将能够制定出治疗乳腺癌的策略，在有更大治愈机会的早期治疗乳腺癌。所有浸润性乳腺癌都起源于上皮细胞，正常乳腺上皮细胞在导管和小叶内呈明显的极化排列。细胞极性和组织的变化是病理学家用于癌症分级的关键标准，支持细胞极性和组织的调节是癌症进展的关键组成部分的概念。然而，我们对调控细胞极性变化的分子机制知之甚少。我相信，癌症中极性通路改变的机制代表了癌细胞生物学中尚未开发的领域，为发现早期诊断和治疗的新策略提供了巨大的潜力，从而有效地根除浸润性乳腺癌。在过去的资助期内，我们发现ErbB2直接与Par6/aPKC极性复合物相互作用。这一途径是ErbB2破坏细胞极性和抑制细胞死亡的能力所必需的，但对于诱导细胞增殖是必不可少的。这些结果已经确定了ErbB2阳性乳腺癌极性通路的两个主要作用：1)破坏细胞和组织结构；2)抑制细胞死亡。后者是一个出乎意料的发现，之前在果蝇和蠕虫身上进行的所有研究都没有预测到这一点。在本研究中，我们将在这些发现的基础上进一步深入了解ErbB2与极性蛋白相互作用的机制，并确定ErbB2- par6极性复合物下游调控细胞死亡的途径。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在体内的相关性，而且还将作为临床前研究的工具。除此之外，我们还建议扩大研究范围，研究极性通路的改变如何促进侵袭性进展和转移。因此，我相信我们的提议采取了一种创新的策略，并利用了癌症生物学的一个尚未开发的领域，目标是找到一类新的生物标志物和药物靶点。

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.