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: 8191627
• 负责人: LI TANG
• 金额: $ 7.69万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191627
• 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. PUBLIC HEALTH RELEVANCE: Project Narrative The proposed study, for the first time, links racial disparity in prevalence of full-length functional human endogenous retrovirus (HERVs) and breast cancer risk and aggressive characteristics between European American (EA) and African American (AA) women. Considering the striking similarities in breast cancer characteristics between sub-Saharan African women and AA women, ancestry components such as HERVs could play a role in understanding racial disparities in breast cancer between AA and EA women. More importantly, the study is likely to have significant impact on women's health, because the findings may help to help target high risk populations and lead to potential intervention strategies for those most at risk.

描述（由申请人提供）：欧洲裔美国 (EA) 和非洲裔美国 (AA) 女性之间明显存在乳腺癌的种族差异，但其潜在机制尚不清楚。拟议的研究旨在调查非洲裔女性中功能性人内源性逆转录病毒（HERV）的高患病率是否会导致 AA 和 EA 女性乳腺癌的发病年龄和侵袭性差异。 HERV 序列是人类基因组中逆转录病毒古代种系感染的残余物。尽管大多数 HERV 因突变而丧失功能，但一些 HERV 仍然具有转录活性，并且有可能干扰宿主功能并导致癌症等疾病。其中，HERV-K113和-K115与乳腺癌的关系特别令人感兴趣，因为：（1）两者都显示出显着的原病毒完整结构，并保留了编码功能性逆转录病毒蛋白的能力； (2) 两者均与小鼠乳腺肿瘤病毒（MMTV）表现出高度的遗传同源性，MMTV是一种能够引起小鼠乳腺肿瘤的逆转录病毒； (3) 两者都是插入多态性，显示非洲和欧洲人群之间的患病率存在​​明显的种族差异。在乳腺肿瘤发生过程中，HERV 可被激活以表达致癌或免疫抑制蛋白，进而促进肿瘤发生。雌激素和其他类固醇治疗似乎可以大大增强乳腺癌细胞中 HERV 的表达。考虑到 AA 和 EA 女性之间荷尔蒙和生殖因素的显着差异，许多已知的荷尔蒙相关暴露可能是乳腺癌的危险因素（例如首次足月妊娠年龄、产次、初潮提前和月经推迟）。更年期），可能与 HERV 相互作用，导致乳腺癌。我们的假设是，AA 和 EA 女性之间 HERV-K113 和 -K115 插入多态性的患病率不同，这种差异分布与乳腺癌风险以及乳腺癌特征的差异相关。拟议的研究将了解 AA 和 EA 女性中 HERV-K113 和 -K115 插入多态性的分布，以检查它们与 EA 和 AA 女性的乳腺癌风险 (Aim1) 以及早发型和侵袭性特征 (Aim2) 的关联与激素相关因素的相互作用（目标3）。该研究将嵌套在正在进行的针对 AA 和 EA 女性乳腺癌的多中心病例对照研究中，总共将包括 1600 名 AA 女性和 1600 名 EA 女性。这是第一个调查 HERV 在人类癌症中作用的大规模流行病学研究。我们也是第一个在种族差异背景下研究 HERV 插入多态性与乳腺癌之间关联的人。这些发现将为了解 AA 女性中早发、侵袭性乳腺癌的患病率提供有价值的信息，并帮助瞄准高危人群，并为高危人群制定潜在的干预策略。 公共健康相关性：项目叙述拟议的研究首次将欧洲裔美国人 (EA) 和非裔美国人 (AA) 之间全长功能性人内源性逆转录病毒 (HERV) 患病率的种族差异与乳腺癌风险和侵袭性特征联系起来女性。考虑到撒哈拉以南非洲女性和 AA 女性在乳腺癌特征上的惊人相似性，HERV 等血统成分可能有助于理解 AA 和 EA 女性乳腺癌的种族差异。更重要的是，这项研究可能会对女性健康产生重大影响，因为研究结果可能有助于瞄准高危人群，并为高危人群制定潜在的干预策略。