Regulation of Mammary Cell Proliferation by Apical Polarity Proteins

描述(申请人提供)：乳腺癌是女性癌症死亡的主要原因。目前抗击乳腺癌的策略主要针对晚期恶性肿瘤以延长生命；因此，它们往往无法导致无病生存。虽然对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，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。这项研究通过定义早期细胞分化的丧失如何与接头蛋白AMOT诱导异常增殖相协调来解决这个问题。因为顶极的破坏是细胞对促生长信号敏感的最早的必要步骤之一，这样的研究可以解释利用ErbB型受体酪氨酸激酶进行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一种细胞机制联系起来，假设极性蛋白诱导MAPK的长时间激活。这与一些报道一致，即RAS和ERK1/2必须针对内小体，才能经历细胞增殖所需的长期激活。这一模型对于促进ErbB2和三阴性乳腺癌的形成和发展的意义将被研究。

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.