Mechanisms by which Polarity Proteins Regulate Initiation and Progression of Brea

几乎所有的恶性乳腺癌都起源于腺体结构内的上皮细胞。正常 上皮结构/极性对于维持细胞与其细胞之间的微妙平衡是至关重要的。 微环境;这种平衡的破坏可能导致在细胞生长过程中观察到的异常细胞行为。 癌的发生和发展。事实上，病理学家通常使用细胞和组织的变化 了解癌症进展并评估治疗方案。尽管 认识到细胞结构的重要性，细胞和组织结构的机制， 在癌症中的破坏仍然知之甚少。很有可能了解这些分子机制 在癌症中细胞、组织和结构的失调不仅能让我们有更好的 了解肿瘤微环境的变化，还可以确定一类新的生物标志物和药物 目标的 在过去的资助期间，我们发现癌基因与极性调节因子相互作用， 破坏细胞极性和上皮结构的三维组织。到交互 不依赖于癌基因诱导细胞增殖的能力。令人惊讶的是， 保护细胞免于凋亡需要基因相互作用。因此，极性基因在其中起着重要的作用 在癌症中。它们是癌基因诱导细胞和组织结构变化以及 保护细胞免于死亡。我认为我们才刚刚开始破冰， 极性通路在启动过程中与癌基因合作的分子机制， 癌的进展。 在本建议书中，我们以上一个资助期的结果为基础，解决以下问题： 深入了解ErbB 2与极性通路相互作用的机制;（2） 确定极性通路如何保护细胞免于凋亡，以及在细胞凋亡过程中起什么作用。 （3）确定极性通路如何与ErbB 2合作以促进 上皮向间质转化和恶性进展。 因此，本提案的目标是采取一个新的视角-了解癌症的发生和发展。 作为细胞极性通路失调的函数的进展。

Almost all malignant breast cancers originate from epithelial cells within glandular structures. Normal epithelial architecture/polarity is critical to maintain the delicate balance between a cell and its microenvironment; disruption of this balance can result in the aberrant cell behavior observed during initiation and progression of carcinoma. In fact, pathologists routinely use changes in cell and tissue architecture to understand cancer progression and make assessments for treatment options. Despite the appreciation of the importance of cell architecture, the mechanism by which cell and tissue architecture is disrupted in carcinoma remains poorly understood. It is likely that understanding the molecular mechanisms by which cell and tissue and architecture is deregulated in carcinoma will not only allow us to have a better understanding of changes in tumor microenvironment but also identify a new class of biomarkers and drug targets. During the past funding period we discovered that oncogenes interact with polarity regulators to disrupt cell polarity and three-dimensional organization of epithelial structures. The interaction was independent of the ability of oncogenes to induce cell proliferation. Surprisingly, the oncogene-polarity genes interaction was required for protecting cells from apoptosis. Thus, polarity genes play important roles in carcinoma. They are required for oncogenes to induce changes in cell and tissue architecture and for protecting cells from death. I think we have just begun to scrape the ice, much remains to be understood on the molecular mechanisms by which polarity pathways cooperate with oncogenes during initiation and progression of carcinoma. In this proposal we build on our results from the previous funding period to address the following: 1) Develop a deeper understanding of the mechanism by which ErbB2 interacts with polarity pathways; (2) Determine how polarity pathways protects cells from apoptosis and what roles does this play during development of drug resistance (3) Determine how polarity pathways cooperate with ErbB2 to promote epithelial to mesenchymal transition and malignant progression. Thus the goal of this proposal is to take a new perspective - understand carcinoma initiation and progression as a function of deregulated cell polarity pathways.