Alcohol and Breast Cancer

描述(申请人提供)：饮酒促进人类癌症的发展，环境因素在病因中起着重要作用。流行病学研究表明，饮酒不仅会增加患乳腺癌的风险，还会加剧现有乳腺肿瘤的进展和侵袭性。尽管如此，酒精促进乳腺肿瘤发生或发展的机制尚未建立。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基因扩增，这与预后不良有关。我们先前已经证明，ErbB2的过表达可以敏化乳腺癌细胞对酒精诱导的促癌作用。最近，我们在ErbB2信号通路中发现了一种可能调节癌细胞侵袭性的新成分，即p38？我们假设酒精增加了依赖于NOX的ROS的产生，ROS激活了ErbB2或MKK6。ErbB2和MKK6的激活导致p38？它招募了SAP97/DLG。活化的SAP97/DLG促进上皮向间充质转化，增加肿瘤干细胞(CSC)的数量和乳腺癌细胞的侵袭力。这导致了攻击性的增强。将有三个具体目标。具体目标1将决定p38的作用？在体外酒精诱导的攻击性。具体目标2将研究酒精诱导p38的潜在机制？以及p38的激活机制是如何的？介导乳腺癌细胞的侵袭性。《特定目标3》将研究p38的作用？在酒精诱导的肿瘤侵袭性动物模型中。这项研究不仅将探索乳腺癌侵袭性的基本细胞生物学，而且还将阐明酒精促进肿瘤作用的机制。这一结果将有助于开发乳腺癌治疗和酒精促进肿瘤的新治疗策略。

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.