Racial disparities in human endogenous retrovirus and breast cancer

人类内源性逆转录病毒和乳腺癌的种族差异

• 批准号: 8319382
• 负责人: LI TANG
• 金额: $ 4.47万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319382
• 关键词: Accounting; Africa; African; African American; Age; Age at First Live Birth; Age at Menarche; American; Area; Breast; Breast Cancer Cell; Breast Cancer Risk Factor; Breast Feeding; Case-Control Studies; Characteristics; Clinical; Diagnosis; Disabled Persons; Disease; Employee Strikes; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Epidermal Growth Factor Receptor; Estrogen Receptor Status; Estrogen Receptors; Estrogens; European; Funding; Genetic; Genetic Polymorphism; Genome; Germ Lines; HERVs; High Prevalence; Hormonal; Hormone replacement therapy; Hormones; Human; Human Genome; Immunosuppressive Agents; Individual; Infection; Intervention; Lead; Length; Logistic Regressions; Malignant Neoplasms; Mammary Neoplasms; Menarche; Menopause; Modeling; Mouse Mammary Tumor Virus; Mus; Mutation; Nonsense Codon; Oncogenic; Phenotype; Population; Pregnancy; Prevalence; Progesterone Receptors; Proteins; Proviruses; Reproductive History; Research; Retroviridae; Retroviridae Infections; Retrovirus Proteins; Risk; Role; Steroids; Structure; Testing; Viral; Woman; anticancer research; breast tumorigenesis; cancer risk; carcinogenesis; design; early onset; high risk; interest; lifestyle factors; malignant breast neoplasm; parity; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Racial disparities in breast cancer clearly exist between European American (EA) and African American (AA) women, but the underlying mechanisms are unknown. The proposed study is designed to investigate whether high prevalence of functional human endogenous retrovirus (HERV) in women of African descent contributes to disparities in age at onset and aggressiveness of breast cancer between AA and EA women. HERV sequences are the remnants of ancient germ line infections by retrovirus in the human genome. Although the majority of HERVs are disabled due to mutation, some of HERVs are still transcriptionally active and have the potential to interfere with host function and cause disease such as cancer. Among them, HERV-K113 and - K115 are of particular interest in relation to breast cancer, because: (1) both show remarkable intact structure of provirus and retain the ability to encode functional retrovirus protein; (2) both display high genetic homology to mouse mammary tumor virus (MMTV), a retrovirus capable of causing mammary tumors in mice; (3) both are insertional polymorphic, showing a clear racial disparity in their prevalence between African and European populations. During breast tumorigenesis, HERVs can be activated to express oncogenic or immunosuppressive proteins, which in turn contribute to tumorigenesis. Expression of HERVs in breast cancer cells appears to be substantially enhanced by treatment with estrogens and other steroids. Considering the significant differences in hormonal and reproductive factors between AA and EA women, it is possible that many known hormone-related exposures that are risk factors for breast cancer (such as age at first full-term pregnancy, parity, early menarche, and late menopause), may interact with HERVs to contribute to breast cancer. Our hypothesis is that the prevalence of HERV-K113 and -K115 insertional polymorphism differs between AA and EA women, and that this differential distribution is associated with breast cancer risk, as well as disparities in breast cancer characteristics. The proposed study will access distribution of insertional polymorphisms of HERV-K113 and -K115 among AA and EA women, to examine their association with breast cancer risk (Aim1) and early-onset and aggressive characteristics (Aim2) in EA and AA women in consideration of interactions with hormone-related factors (Aim3). The study will be nested in the ongoing multi-center case-control study of breast cancer in AA and EA women, and a total of 1600 AA women and 1600 EA women will be included. This is the first large-scale epidemiologic study to investigate the role of HERV in human cancer. We are also the first ones to investigate the association between insertional polymorphism of HERVs and breast cancer in the context of racial disparity. The findings will provide valuable information for understanding the preponderance of early onset, aggressive breast cancer among AA women, and help target high risk populations and lead to potential intervention strategies for those most at risk.

描述（由申请人提供）：乳腺癌的种族差异显然存在于欧美（EA）和非裔美国人（AA）妇女之间，但潜在的机制尚不清楚。拟议的研究旨在调查非洲血统妇女功能性人体内源性逆转录病毒（HERV）的高患病率是否有助于AA和EA妇女之间乳腺癌的侵略性和乳腺癌的侵略性。 HERV序列是人类基因组中逆转录病毒的古代种系感染的残余。尽管大多数HERV由于突变而被禁用，但一些HERV仍具有转录活性，并且有可能干扰宿主功能并引起癌症等疾病。其中，HERV -K113和-K115在与乳腺癌有关的情况下特别感兴趣，因为：（1）两者都表现出明显的Provirus完整结构，并保留编码功能性逆转录病毒蛋白的能力； （2）均与小鼠乳腺肿瘤病毒（MMTV）表现出高遗传同源性，这是一种能够引起小鼠乳腺肿瘤的逆转录病毒； （3）两者都是插入的多态性，在非洲和欧洲人口之间的流行率上显示出明显的种族差异。在乳腺肿瘤发生过程中，可以激活HERV以表达致癌或免疫抑制蛋白，这反过来又导致肿瘤发生。通过用雌激素和其他类固醇的治疗，HERV在乳腺癌细胞中的表达显着增强。考虑到AA和EA妇女之间的激素和生殖因素的显着差异，许多已知的与激素相关的暴露可能是乳腺癌的危险因素（例如，年龄在第一期全学期怀孕，平等，早期，初潮和晚期和晚期，晚期和晚期更年期），可能与HERV相互作用，为乳腺癌做出贡献。我们的假设是，AA和EA妇女之间的HERV -K113和-K115插入多态性的流行率不同，并且这种差异分布与乳腺癌的风险以及乳腺癌特征的差异有关。拟议的研究将获取AA和EA妇女中HERV-K113和-K115的插入多态性的分布，以研究其与EA和AA女性的乳腺癌风险（AIM1）以及早期发作和积极特征（AIM2）的关联（AIM2）与激素相关因素的相互作用（AIM3）。该研究将嵌套在正在进行的AA和EA妇女乳腺癌的多中心病例对照研究中，总共包括1600名AA妇女和1600名EA妇女。这是研究HERV在人类癌症中的作用的首次大规模流行病学研究。我们也是第一个在种族差异的情况下研究HERV和乳腺癌插入多态性之间的关联的人。这些发现将提供有价值的信息，以了解AA妇女早期发作，侵略性乳腺癌的优势，并有助于针对高风险人群，并为最有风险的人提供潜在的干预策略。