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。目前对抗乳腺癌的策略主要针对晚期恶性肿瘤以延长寿命;因此，它们通常不能导致无病生存。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衔接蛋白Amot诱导的异常增殖相协调来解决这个问题。由于顶端极性的分解是细胞对促生长信号敏感的最早的必要步骤之一，因此这些研究可以解释如何形成利用ErbB型受体酪氨酸激酶生长的高度增殖性乳腺癌细胞。我们的模型将这些效应与细胞机制联系起来，认为极性蛋白诱导MAPKs的长期激活。这与Ras和Erk 1/2必须靶向内体以经历细胞增殖所需的延长激活的几个报道一致。该模型对促进ErbB 2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.