Cell polarity pathways and ErbB2 mediated tumorigenesis

目前乳腺癌的治疗策略大多旨在控制恶性疾病。 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，通过了解与糖尿病的发生有关的分子机制， 癌前病变和进展到恶性肿瘤，我们将能够制定治疗策略 乳腺癌越早治愈的机会越大。所有浸润性乳腺癌都起源于 正常乳腺中的上皮细胞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结构的调节是一个关键组成部分的概念 癌症的进展。然而，人们对调节变化的分子机制知之甚少。 在细胞的极性上。我认为，癌症中极性通路被改变的机制代表了一种 尚未开发的癌细胞生物学领域，为发现治疗癌症的新策略提供了巨大的潜力 早期诊断和治疗，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是破坏细胞极性和抑制细胞的能力所必需的途径 死亡，但对诱导细胞增殖是可有可无的。这些结果确定了以下两个主要角色 ErbB2阳性乳腺癌中的极性通路：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 在果蝇和蠕虫身上进行。 在这项提案中，我们建议对这些发现进行扩展，并加深对 ErbB2与极性蛋白相互作用的机制及其下游的识别途径 ERBB2-PAR6极性复合体，调节细胞死亡。在这些研究的过程中，我们将制定 强大的体内模型，不仅允许我们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。除上述外，我们还建议扩大范围和 研究极性通路的改变如何促进侵袭性进展和转移。因此，我 我相信我们的提案采取了一种创新的战略，并利用了癌症生物学中一个未知的领域 目标是找到一类新的生物标记物和药物靶标。

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.