Alcohol and Breast Cancer

Alcohol consumption not only increases breast cancer risk, but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless, the mechanisms by which alcohol contributes to breast tumor initiation or progression are unclear. ErbB2 (HER2) 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 effector kinase in ErbB2 signaling pathway that may mediate alcohol-enhanced cancer cell aggressiveness, the p38£^. p38£^ is one of four p38 MAPK isoforms; others are p38£\, £] and £_. Most research of p38 MAPK focuses on p38£\ and £]; p38£^ receives little attention. Our preliminary data indicated that alcohol selectively activated p38£^ƒn. We hypothesize that alcohol-promoted aggressivenes of breast cancer is mediated by p38£^ and it dowstream SAP97/DLG . We propose three specific aims. Specific Aim 1: Specific Aim 1: To determine the role of p38£^ in alcohol-induced aggressiveness in vitro. Specific Aim 2: To investigate the mechanisms underlying alcohol-induced p38£^ activation as well as the mechanisms how p38£^ mediates aggressiveness of breast cancer cells. Specific Aim 3: To investigate the role of p38£^ in alcohol-induced tumor aggressiveness in vivo. Together, these studies will establish a novel signaling pathway (ErbB2/p38£^) that regulates the aggressiveness of breast cancer and identify the cellular target of alcohol exposure. 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 therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.