ALCOHOL AND BREAST CANCER

流行病学和临床研究表明，酒精滥用促进乳房发育 癌酒精诱发的肿瘤促进有两个特点：1）饮酒增加风险 2）酒精促进癌症进展，并与更积极的形式有关。 乳腺癌因此，酒精暴露可能影响乳腺肿瘤发展的两个阶段，即， 肿瘤发生（细胞转化和肿瘤的发作）和癌症侵袭（肿瘤生长、转移和转移）。 耐药性/复发）。青少年饮酒是世界范围内的一个严重问题。饮酒年龄是 越来越年轻，而每次饮酒量增加。青少年 饮酒是事故、伤害、精神疾病或某些慢性疾病的危险因素， 病理学，以及成瘾的外观，包括酗酒。虽然有害影响 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 虽然已经有了很好的研究，但它对肿瘤风险的影响从未被探索过。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，青春期小鼠对酒精的促肿瘤作用更敏感 比成年老鼠。我们的研究结果表明，酒精诱导的肿瘤发生和进展/侵袭性可能 通过不同的机制运作。p21激活激酶（PAK）是丝氨酸/苏氨酸激酶家族; PAK 1和PAK 4在乳腺肿瘤的发生过程中有重要作用。有四个成员 哺乳动物p38丝裂原活化蛋白激酶（MAPK）家族的四个成员，即p38α、p38β、p38 β和p38δ。 虽然它们的某些生理功能可能重叠，但这些MAPK的作用是完全不同的。 p38激酶MAPK被认为参与乳腺癌的进展/侵袭性。中央 这一建议的假设是，酒精促进的乳腺肿瘤发生和侵袭性是介导的， 通过不同的机制：酒精诱导的肿瘤发生主要由PAK 1/PDK 4介导， 雌激素/孕激素信号通路在青少年，而酒精诱导的攻击性主要是 通过p38介导的MAPK信号通路。我们还假设，青少年的敏感性增强， 酒精是由于调节乳腺发育的信号通路更多， 对酒精敏感。本提案将使用体外和体内方法来检验这一假设。 这项提案将首次调查青少年酒精暴露对发展的影响， 乳腺和肿瘤发生/进展。它不仅能阐明细胞和分子 酒精介导的肿瘤促进机制，但也有助于开发治疗策略， 治疗酒精促进乳腺癌。

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.