Alcohol and Breast Cancer

描述（由申请人提供）：酒精消费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，饮酒不仅会增加乳腺癌的风险，而且还会促进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进展的机制尚未确定。ErbB 2是表皮生长因子受体家族成员。ErbB 2扩增在20-30%的乳腺癌患者中发现，并与预后不良相关。我们之前已经证明ErbB 2的过表达会使乳腺癌细胞对酒精诱导的肿瘤促进敏感。最近，我们发现了ErbB 2信号通路中的一种新组分，它可能调节癌细胞的侵袭性，即p38？。我们假设酒精增强了NOX依赖的ROS产生，从而激活ErbB 2或MKK 6。ErbB 2和MKK 6的激活导致p38？SAP 97/DLG。活化的SAP 97/DLG促进上皮向间充质转化（EMT），增加癌症干细胞（CSC）群体和乳腺癌细胞的侵袭性。这导致了更强的侵略性。将有三个具体目标。具体目标1将决定p38的作用？酒精诱导的攻击性具体目标2将探讨酒精诱导的p38？激活以及机制如何p38？介导乳腺癌细胞的侵袭性。具体目标3将研究p38的作用？酒精诱导的肿瘤侵袭性。这项研究不仅将探索乳腺癌侵袭性的基本细胞生物学，还将阐明酒精促进肿瘤作用的机制。这些结果将有助于为乳腺癌治疗和酒精介导的肿瘤促进开发新的治疗策略。

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.