Regulation of Mammary Cell Proliferation by Apical Polarity Proteins

描述（由申请人提供）：乳腺癌是女性癌症死亡的主要原因。目前防治乳腺癌的策略主要针对晚期恶性肿瘤，以延长寿命；因此，它们往往不能实现无病生存。虽然癌前病变的检测越来越准确，但无法预测哪些癌前病变会导致肿瘤生长，这阻碍了识别可能发展为侵袭性肿瘤的患者或预防这种情况的药物的努力。本研究通过定义细胞分化的早期丧失如何与适配器蛋白Amot诱导的异常增殖相协调来解决这一问题。由于顶端极性的破坏是细胞对促生长信号敏感的最早必要步骤之一，这些研究可能解释了利用ErbB型受体酪氨酸激酶生长的高增殖乳腺癌细胞是如何形成的。我们的模型将这些效应与细胞机制联系起来，假设极性蛋白诱导MAPKs的长时间激活。这与一些报道一致，Ras和Erk1/2必须靶向内体才能经历细胞增殖所需的长时间激活。该模型对促进ErbB2和三阴性型乳腺癌的形成和进展的影响将被研究。

DESCRIPTION (provided by applicant): Breast cancer is a leading cause of cancer death among women. Current strategies to combat breast cancer mainly target late stage malignancies to extend lifespan; consequently, they often fail to result in disease free survival. While detection of pre-malignant lesions is increasingly accurate, the inability to predict which precancerous lesions lead to neoplastic growth has impeded efforts to identify patients that are likely to develop aggressive neoplasms or drugs to prevent this. This study addresses this issue by defining how the early loss of cellular differentiation is coordinated with the induction of aberrant proliferation by the adaptor protein Amot. Because the breakdown of the apical polarity is one of the earliest essential steps for cells to be sensitized to pro-growth signaling, such studies may explain how highly proliferative breast cancer cells that utilize ErbB type receptor tyrosine kinases for growth are formed. Our model relating these effects to a cellular mechanism posits that polarity proteins induce the prolonged activation of MAPKs. This is consistent with several reports that Ras and Erk1/2 must be targeted to endosomes to undergo prolonged activation that is required for cellular proliferation. The implications of this model for promoting the formation and progression of ErbB2 and triple negative type breast cancers will be investigated. PUBLIC HEALTH RELEVANCE: A majority of the 40,000 mortalities from breast cancer each year follow therapeutic strategies that target late stage malignant tumors. The premise of this proposal is that long-term survival could be substantially improved if early hyperplastic lesions were prevented from developing into aggressive cancers; a process that is mainly characterized by the loss of epithelial architecture and aberrant cellular accumulation. To this end, this study will investigate a novel mechanism whereby loss of cellular shape directly regulates cell growth to promote early initiation of cellular proliferation and invasiveness.