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/极性对于维持细胞和细胞之间的微妙平衡至关重要。 微环境；这种平衡的破坏会导致观察到的异常细胞行为 癌症的发生和发展。事实上，病理学家经常使用细胞和组织的变化 架构以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，即细胞和组织结构形成的机制 在癌症中的干扰仍然知之甚少。很可能对分子机制的理解 通过在癌症中解除对细胞、组织和结构的调控，不仅可以让我们有更好的 了解肿瘤微环境的变化还能识别一类新的生物标志物和药物 目标。 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 破坏细胞的极性和上皮结构的三维组织。互动是 不依赖于癌基因诱导细胞增殖的能力。令人惊讶的是，致癌基因的极性 基因的相互作用是保护细胞免受凋亡的必要条件。因此，极性基因扮演着重要的角色。 在癌症中。它们是癌基因诱导细胞和组织结构改变所必需的，并对 保护细胞免于死亡。我想我们才刚刚开始摸索，还有很多事情要弄清楚 极性通路与癌基因协同作用的分子机制 癌症的进展。 在本提案中，我们在上一次筹资期间取得的成果的基础上，解决以下问题：1) 加深对ErbB2与极性通路相互作用机制的理解；(2) 确定极性通路是如何保护细胞免受凋亡的，以及这在 耐药的发生(3)决定极性通路如何与ErbB2协同促进 上皮向间充质转化和恶性进展。 因此，这项建议的目标是采取一个新的视角-理解癌症的起源和 作为去调控的细胞极性途径的函数的进展。

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.