Alcohol and Breast Cancer

Epidemiological and clinical studies indicate that alcohol abuse promotes the development of breast cancer. There are two features of alcohol-induced tumor promotion: 1) alcohol consumption increases the risk of breast cancer; 2) alcohol promotes cancer progression and is associated with more aggressive forms of breast cancer. Therefore, alcohol exposure could affect both phases of mammary tumor development, namely, tumorigenesis (cell transformation and onset of tumor) and cancer aggression (tumor growth, metastasis, and drug resistance/recurrence). Adolescent alcohol drinking is a serious problem in the U.S., and adolescent drinking is on the rise, and drinking age is getting younger. Although the harmful effect of adolescent alcohol exposure on cognitive deficits and addiction has been well documented, its effect on tumor risk has never explored. Our study indicated that adolescent mice were more sensitive to alcohol tumor promoting effect than adult mice. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Our findings suggest that alcohol-induced tumorigenesis and aggressiveness may operate in different mechanisms. The p21 Activated Kinases (PAKs) are a family of serine threonine kinases; PAK1 and PAK4 are particularly implicated in the carcinogenesis of mammary tumor. We showed that PAK1 was affected by alcohol in the adolescent mice. There are four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family, namely, p38á, p38â, p38ã and p38ä. Although some of their physiological functions may overlap, the role of these MAPKs is quite different. Our previous results suggested that p38ã MAPK was involved in the progression and aggressiveness of breast tumor. The central hypothesis for this proposal is that alcohol-promoted mammary tumorigenesis and aggressiveness is mediated by different mechanisms: alcohol-induced tumorigenesis is mainly mediated by PAK1/PDK4 and estrogen/progestrone signaling pathway, while alcohol-induced aggressiveness is mediated by p38ã MAPK signaling pathway. We also hypothesize that the enhanced sensitivity of adolescent to alcohol is due that the signaling pathways regulating the development of mammary glands are more affected by alcohol. We proposed three specific aims to test this hypothesis using both in vitro and in vivo approaches. This proposal will for the first time investigate the impact of adolescent alcohol exposure on tumor development, and the process of tumorigenesis and progression may be regulated by different mechanisms. This proposal will tease out the effect of alcohol on tumorigenesis and progression, and provide valuable models to examine the cellular and molecular mechanisms underlying these two different processes. It will be helpful developing strategies for treating alcohol-promoted tumor aggressiveness.