Alcohol and Breast Cancer

描述（申请人提供）：饮酒促进人类癌症的发展，环境因素在病因学中起重要作用。流行病学研究表明，饮酒不仅会增加患乳腺癌的风险，还会加快现有乳腺肿瘤的进展和侵袭性。尽管如此，酒精导致乳腺肿瘤发生或发展的机制尚未确定。ErbB2是表皮生长因子受体家族的成员。在20-30%的乳腺癌患者中发现ErbB2扩增，并与预后不良相关。我们之前已经证明，ErbB2的过度表达使乳腺癌细胞对酒精诱导的肿瘤促进敏感。最近，我们在ErbB2信号通路中发现了一个可能调节癌细胞侵袭性的新成分p38？我们假设酒精可以增强一氧化氮依赖性ROS的产生，从而激活ErbB2或MKK6。ErbB2和MKK6的激活导致p38？招募SAP97/DLG。活化的SAP97/DLG促进上皮细胞向间充质细胞转化（EMT），增加癌症干细胞（CSC）的数量和乳腺癌细胞的侵袭性。这导致了侵略性的增强。将有三个具体目标。特异性Aim 1将决定p38的作用。酒精诱导的体外侵袭性。特异性目标2将研究酒精诱导p38？激活以及p38的机制是怎样的？介导乳腺癌细胞的侵袭性。特异性Aim 3将研究p38？酒精诱导的肿瘤侵袭性动物模型。本研究不仅将探索乳腺癌侵袭性的基本细胞生物学，还将阐明酒精促瘤作用的机制。结果将有助于开发新的治疗策略乳腺癌治疗和酒精介导的肿瘤促进。

DESCRIPTION (provided by applicant): Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk, but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless, the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently, we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness, the p38?. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38? which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT), increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38? in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38? activation as well as the mechanisms how p38? mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38? in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness, but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.