ALCOHOL AND BREAST CANCER

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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 worldwide. The drinking age is getting younger while the amount of alcohol uptake per occasion has increased. Adolescent alcohol consumption is a risk factor for accidents, injuries, mental illnesses or some chronic diseases and pathologies, as well as for the appearance of addictions, including alcoholism. Although the harmful effect of adolescent alcohol exposure on the brain structures and behaviors, such as cognitive deficits and addiction has been well studied, its effect on tumor risk has never explored. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. The adolescent is a critical period of mammary gland development. Our study indicated that adolescent mice were more sensitive to alcohol tumor promoting effect than adult mice. Our findings suggest that alcohol-induced tumorigenesis and progression/aggressiveness may operate by 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. There are four members of the mammalian p38 mitogen-activated protein kinase (MAPK) family, namely, p38α, p38β, p38 and p38δ. Although some of their physiological functions may overlap, the role of these MAPKs is quite different. p38MAPK has been suggested to involve in the progression/aggressiveness of breast cancer. 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 in the adolescents, while alcohol-induced aggressiveness mainly is mediated by p38MAPK signaling pathway. We also hypothesize that the enhanced sensitivity of adolescent to alcohol is due to that the signaling pathways regulating the development of mammary glands are more sensitive to alcohol exposure. This proposal will test the hypothesis using both in vitro and in vivo approaches. This proposal will for the first time investigate the impact of adolescent alcohol exposure on the development of mammary glands and tumorigenesis/progression. It will not only elucidate the cellular and molecular mechanisms underlying alcohol-mediated tumor promotion, but also help to develop therapeutic strategies for treating alcohol promotion of breast cancer.