Cell polarity pathways and ErbB2 mediated tumorigenesis

目前乳腺癌的治疗策略主要是针对控制恶性疾病。 在大多数情况下，这些策略延长了患者的寿命，但很少能成功阻止癌症。 我相信，通过了解参与发展的分子机制， 癌前病变和恶性肿瘤的进展，我们将能够制定治疗策略， 早期乳腺癌，治愈的机会更大。所有侵袭性乳腺癌都起源于 上皮细胞，其在正常乳腺中在导管内以明显的极化组织排列 和小叶。细胞极性和组织的变化是病理学家在分级时使用的关键标准 癌症，支持细胞极性和组织组织的调节是一个关键组成部分的概念 癌症进展的迹象。然而，人们对调节变化的分子机制知之甚少， 在细胞极性中。我相信，癌症中极性通路改变的机制代表了一种 这是一个尚未开发的癌细胞生物学领域，为发现新的治疗策略提供了巨大的潜力。 早期诊断和治疗，以有效根除浸润性乳腺癌。 在过去的资助期间，我们发现ErbB2直接与Par6/aPKC相互作用， 极性复合体ErbB2破坏细胞极性和抑制细胞凋亡的能力需要这一途径。 死亡，但不诱导细胞增殖。这些结果确定了两个主要作用， 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意想不到的发现，这是以前所有研究都没有预测到的 在果蝇和蠕虫中进行。 在本提案中，我们建议在这些发现的基础上进行扩展，并加深对 ErbB2与极性蛋白相互作用的机制，并确定ErbB2下游的途径。 ErbB2-Par6极性复合物，调节细胞死亡。在这些研究的过程中，我们将开发 强大的体内模型，不仅使我们能够确定我们的发现在体内的相关性， 作为临床前研究的工具。此外，我们亦建议扩大范围， 研究极性途径的改变如何促进侵袭性进展和转移。所以我 我相信，我们的建议采取了一种创新的策略，并利用了癌症生物学的一个未开发的领域 其目标是找到一类新的生物标志物和药物靶点。

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.