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，酗酒会促进乳房的发展 癌症。酒精引起的肿瘤促进有两个特征：1）饮酒增加风险 乳腺癌； 2）酒精促进癌症的进展，并与更具侵略性的形式相关 乳腺癌。因此，酒精暴露可能会影响乳腺肿瘤发育的两个阶段，即 肿瘤发生（肿瘤的细胞转化和发作）和癌症侵袭性（肿瘤生长，转移和 耐药性/复发）。青少年饮酒是全球一个严重的问题。饮酒年龄是 每次饮酒量增加，而每次摄入量就增加了。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， 病理学以及成瘾的出现，包括酗酒。虽然有害效果 大脑结构和行为上的青少年酒精暴露，例如认知定义和成瘾 研究良好，其对肿瘤风险的影响从未探索过。分子机制 但是，促进酒精肿瘤尚不清楚。青少年是乳腺的关键时期 发展。我们的研究表明，青少年小鼠对促进酒精肿瘤的效果更敏感 比成年小鼠。我们的发现表明，酒精引起的肿瘤发生和进展/侵略性可能 通过不同的机制运行。 p21活化激酶（PAKS）是丝氨酸苏氨酸激酶家族。 PAK1和PAK4尤其与乳腺肿瘤的致癌作用有关。有四个成员 哺乳动物p38有丝分裂原激活的蛋白激酶（MAPK）家族的含量，即p38α，p38β，p38和p38δ。 尽管他们的某些物理功能可能重叠，但这些MAPK的作用却大不相同。 p38MAPK被建议参与乳腺癌的进展/侵略性。中央 该提议的假设是介导酒精促进的乳腺肿瘤发生和侵略性 通过不同的机制：酒精诱导的肿瘤发生主要由PAK1/PDK4和 青少年中的雌激素/配源信号通路，而酒精引起的侵略性主要是 由p38MAPK信号通路介导。我们还假设青少年的灵敏度增强 酒精是由于调节乳腺发育的信号通路更多 对酒精暴露敏感。该建议将使用体外和体内方法测试假设。 该提案将首次研究青少年酒精暴露对发展的影响 乳腺和肿瘤发生/进展。它不仅会阐明细胞和分子 酒精介导的肿瘤促进的机制，但也有助于制定理论策略 治疗酒精促进乳腺癌。