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.
Excessive alcohol consumption is associated with advanced and aggressive breast cancers, suggesting that alcohol may enhance mammary tumor progression and metastasis. We found that p38? signaling is down stream of ErbB2 and hypothesize that alcohol activates p38? which promotes tumor aggressiveness and accelerates mammary tumor development. This proposal will elucidate the mechanisms by which alcohol promotes the progression of mammary tumors and identify therapeutic targets for alcohol-associated tumor promotion.
|Xu, Mei; Chen, Gang; Fu, Wei et al. (2012) Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis. Toxicol Sci 127:42-53|
|Luo, Jia (2012) Mechanisms of ethanol-induced death of cerebellar granule cells. Cerebellum 11:145-54|
|Yang, Guang; Meng, Ya; Li, Wenxia et al. (2011) Neuronal MCP-1 mediates microglia recruitment and neurodegeneration induced by the mild impairment of oxidative metabolism. Brain Pathol 21:279-97|
|Chen, Gang; Luo, Jia (2010) Anthocyanins: are they beneficial in treating ethanol neurotoxicity? Neurotox Res 17:91-101|
|Xu, Mei; Bower, Kimberly A; Chen, Gang et al. (2010) Ethanol enhances the interaction of breast cancer cells over-expressing ErbB2 with fibronectin. Alcohol Clin Exp Res 34:751-60|
|Xu, Mei; Bower, Kimberly A; Wang, Siying et al. (2010) Cyanidin-3-glucoside inhibits ethanol-induced invasion of breast cancer cells overexpressing ErbB2. Mol Cancer 9:285|
|Luo, Jia (2009) GSK3beta in ethanol neurotoxicity. Mol Neurobiol 40:108-21|
|Luo, Jia (2009) Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett 273:194-200|