ALCOHOL AND BREAST CANCER

流行病学和临床研究表明，酗酒促进乳房发育 癌症。酒精诱导的促癌有两个特点：1)饮酒会增加风险 2)酒精促进癌症的进展，并与更具侵袭性的 乳腺癌。因此，酒精暴露可能会影响乳腺肿瘤发展的两个阶段，即， 肿瘤发生(细胞转化和肿瘤发病)和癌症侵袭(肿瘤生长、转移和 耐药/复发)。青少年饮酒是一个严重的世界性问题。饮酒年龄是 变得越来越年轻，而每次饮酒量却有所增加。青少年 饮酒是事故、伤害、精神疾病或一些慢性病的危险因素 病理，以及成瘾的出现，包括酗酒。虽然这个游戏的有害影响 青少年酒精暴露对大脑结构和行为的影响，如认知缺陷和成瘾 已经得到了很好的研究，但它对肿瘤风险的影响从未被探索过。潜在的分子机制 然而，酒精对肿瘤的促进作用仍不清楚。青春期是乳腺发育的关键时期 发展。我们的研究表明，青春期小鼠对酒精促进肿瘤的作用更敏感 而不是成年老鼠。我们的发现表明，酒精诱导的肿瘤发生和进展/侵袭性可能 由不同的机制运作。P21激活的蛋白激酶(PAK)是一个丝氨酸苏氨酸激酶家族； PAK1和PAK4与乳腺肿瘤的发生密切相关。有四名成员 哺乳动物p38丝裂原活化蛋白激酶家族，即p38α、p38β、p38和p38δ。 虽然它们的一些生理功能可能会重叠，但这些MAPK的作用却截然不同。 P38MAPK被认为与乳腺癌的进展/侵袭性有关。中环 这一提议的假设是酒精促进的乳腺肿瘤的发生和侵袭性是由 不同机制：酒精诱导的肿瘤发生主要由PAK1/PDK4和 雌激素/孕激素在青少年中的信号转导途径，而酒精诱导的攻击性主要是 由p38MAPK信号通路介导。我们还假设，青少年敏感度的增强 酒精是由于调控乳腺发育的信号通路较多 对酒精暴露敏感。这项提议将使用体外和体内方法来检验这一假说。 这项提案将首次调查青少年酒精暴露对青少年精神疾病发展的影响 乳腺与肿瘤的发生/发展。它不仅将阐明细胞和分子 酒精促进肿瘤的潜在机制，但也有助于开发治疗策略 治疗促进乳腺癌的酒精。

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.