ALCOHOL AND BREAST CANCER

酒精与乳腺癌

• 批准号: 10165414
• 负责人: JIA LUO
• 金额: $ 34.16万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10165414
• 关键词: Accidents; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Aggressive behavior; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Appearance; Behavior; Behavior Disorders; Brain; Breast Cancer Model; Breast Cancer Risk Factor; Breast Cancer cell line; Breast Epithelial Cells; Chronic; Chronic Disease; Clinical Research; Cognitive deficits; Development; Diagnosis; Disease; Drug resistance; Estrogens; Family; Female; Funding; In Vitro; Individual; Injury; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mental disorders; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Pathology; Pathway interactions; Phase; Physiological; Prevalence; Process; Protein-Serine-Threonine Kinases; Recurrence; Risk; Risk Factors; Role; Signal Pathway; Structure; Testing; Therapeutic; Time; Transgenic Mice; Treatment outcome; Tumor Promotion; United States; Vulnerable Populations; Woman; addiction; adolescent alcohol effect; adolescent alcohol exposure; aged; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol risk; binge drinking; brain behavior; breast cancer progression; cancer risk; cell transformation; critical period; drinking; epidemiology study; in vitro Model; in vivo; malignant breast neoplasm; mammary gland development; member; neoplastic cell; novel; p21 activated kinase; p38 Mitogen Activated Protein Kinase; tumor; tumor growth; tumor progression; tumorigenesis; underage drinking; uptake; young adult

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.

流行病学和临床研究表明，酗酒可促进乳腺发育 酒精诱发肿瘤有两个特点：1）饮酒增加风险。 乳腺癌；2) 酒精会促进癌症进展，并与更具侵袭性的癌症相关 因此，接触酒精可能会影响乳腺肿瘤发展的两个阶段，即： 肿瘤发生（细胞转化和肿瘤发生）和癌症侵袭（肿瘤生长、转移和 耐药性/复发）。青少年饮酒是世界范围内的一个严重问题。 年龄越来越小，而青少年每次饮酒的量却增加了。 饮酒是发生事故、受伤、精神疾病或某些慢性疾病的危险因素 病理，以及成瘾的出现，包括酗酒的有害影响。 青少年酒精暴露对大脑结构和行为的影响，例如认知缺陷和成瘾 已经得到充分研究，但其对肿瘤风险的影响从未被探索过。 然而，酒精对肿瘤的促进作用仍不清楚。青春期是乳腺的关键时期。 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。 我们的研究结果表明，酒精诱导的肿瘤发生和进展/攻击性可能会增加。 p21 激活激酶 (PAK) 是丝氨酸苏氨酸激酶家族； PAK1和PAK4与乳腺肿瘤的癌变密切相关，共有四个成员。 哺乳动物 p38 丝裂原激活蛋白激酶 (MAPK) 家族的成员，即 p38α、p38β、p38 和 p38δ。 尽管它们的一些生理功能可能重叠，但这些 MAPK 的作用却截然不同。 p38MAPK 被认为参与乳腺癌的进展/侵袭性。 该提议的假设是酒精促进乳腺肿瘤的发生和侵袭性是介导的 机制不同：酒精诱发的肿瘤发生主要由PAK1/PDK4介导， 青少年的雌激素/孕激素信号通路，而酒精引起的攻击性主要是 我们还发现青少年的敏感性增强。 酒精是因为调节乳腺发育的信号通路更多 该提案将使用体外和体内方法检验该假设。 该提案将首次调查青少年酒精暴露对发育的影响 乳腺和肿瘤发生/进展不仅会阐明细胞和分子。 酒精介导的肿瘤促进机制，也有助于制定治疗策略 治疗酒精促进乳腺癌。