Relationships between parity, breastfeeding and ER- breast cancer in African American women: Elucidating the biologic underpinnings at the molecular and cellular level.

非裔美国女性的产次、母乳喂养和 ER-乳腺癌之间的关系：阐明分子和细胞水平的生物学基础。

• 批准号: 10057367
• 负责人: Christine B. Ambrosone
• 金额: $ 63.72万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057367
• 关键词: Affect; African; African American; Age; Basal Cell; Biological; Breast; Breast Epithelial Cells; Breast Feeding; Candidate Disease Gene; Cell Differentiation process; Cells; Child; Complement; Complex; DNA Methylation; Data; Data Pooling; Development; Diagnosis; Differentiated Gene; Disease; Epidemiology; Epigenetic Process; Epithelial Cells; Equation; Estrogen Receptor Status; Estrogen receptor negative; Estrogen receptor positive; Etiology; Event; Gene Expression; Gene Expression Profile; Genes; Genetic; Health; High Risk Woman; Human; Hypermethylation; Incidence; Laboratories; Lead; Maintenance; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Methylation; Modeling; Molecular; Molecular Target; Mus; Nulliparity; Pathway Analysis; Pathway interactions; Phenotype; Pilot Projects; Population; Population Group; Prevention; Prevention approach; Prevention strategy; Preventive; Prognosis; Proteins; Public Health; Race; Repression; Reproductive History; Research; Risk; Risk Factors; Sampling; Structure; Subgroup; Tissue Banks; Tissue Model; Woman; Women' s Health; Work; aggressive breast cancer; black women; cancer subtypes; epidemiologic data; epidemiology study; epigenetic silencing; epigenome; genome wide methylation; genome-wide; high risk; human tissue; individualized prevention; malignant breast neoplasm; methylation pattern; mortality; mouse model; novel marker; parity; parous; progenitor; reproductive; stem cells; therapeutic target; tumor; tumor DNA; volunteer

ABSTRACT: African-American (AA) women are more likely than other US groups to be diagnosed with estrogen receptor negative (ER-) breast cancer, with poorer prognosis and higher mortality. Understanding the biological mechanisms underlying ER- breast cancer in AA women and developing effective preventive strategies represents a critical unmet need with major public health implications. We and others have shown that risk of ER- breast cancer is increased among AA women who are parous and do not breastfeed; factors that are more common among AA women, and may help to explain their higher incidence of ER- tumors. We hypothesize that specific reproductive exposures result in epigenetic silencing of pro-luminal differentiation genes via DNA methylation, leading to an expansion of aberrant, maturation-arrested luminal progenitor cells, which can give rise to ER- cancers. Our previous data showed distinct differences in tumor DNA methylation according to ER status. One strong candidate gene derived from these data is FOXA1, which promotes luminal cell differentiation by positively regulating a luminal gene expression signature in progenitor cells and repressing the basal cell phenotype. This gene was hyper-methylated in ER- versus ER+ tumors from AA women, particularly in those who were parous and did not breastfeed. Consistent with inhibitory effects of methylation on gene expression, FOXA1 protein levels were lower in ER- versus ER+ breast tumors, and lower in ER- tumors from parous vs. nulliparous women. Supporting this hypothesis, we recently showed that heterozygous deletion of Foxa1 in the mouse mammary gland results in a dramatic skewing of epithelial cell populations toward luminal progenitors. Building on these preliminary results, we propose a comprehensive genome-wide DNA methylation analysis of tumor samples from 1,621 AA women with breast cancer from the Black Women's Health Study) and the Women's Circle of Health Study using the IIllumina EPIC 850K array. Combining these profiles with existing 450K data from 383 AA cases after methylation imputation, we will examine FOXA1 and differentially methylated loci (DMLs) that distinguish ER subgroups. With epidemiologic data from these 2,004 AA cases, we will assess associations between reproductive risk factors and methylation of FOXA1 and top DMLs, using weighted gene correlation network analysis and structural equation modeling to evaluate complex relationships. We will evaluate the same relationships between parity, breastfeeding and methylation in normal breast tissue donated by healthy AA volunteers to the Komen Tissue Bank. Using mouse models, we will experimentally investigate if parity and breastfeeding influence the methylation level of Foxa1 and other pro-luminal candidate genes, as well as relative proportions of distinct mammary gland epithelial cell populations. This transdisciplinary, multi-pronged approach will enable us to understand the etiology of aggressive breast cancer in AA women, facilitate the development of novel markers for those at highest risk, and uncover promising molecular targets for precision prevention approaches.

摘要：非裔美国人（AA）妇女比其他美国群体更有可能被诊断 雌激素受体阴性（ER-）乳腺癌，预后较差，死亡率更高。了解 AA妇女的ER-乳腺癌的生物学机制并发展有效的预防 策略代表了对主要公共卫生影响的重要需求。我们和其他人已经表明 在众多且不母乳喂养的AA妇女中，ER-乳腺癌的风险增加了；因素 在AA妇女中更常见，可能有助于解释其较高的ER肿瘤发病率。我们 假设特定的生殖暴露会导致丙型分化的表观遗传沉默 通过DNA甲基化基因，导致异常，成熟的腔祖细胞的扩张， 这会引起癌症。我们先前的数据显示肿瘤DNA甲基化明显差异 根据ER状态。从这些数据得出的一个强大的候选基因是FOXA1，它促进了腔 通过在祖细胞和 抑制基底细胞表型。该基因在AA的ER+肿瘤中被过度甲基化 妇女，特别是在那些没有母乳喂养的妇女中。与抑制作用一致 甲基化基因表达，FOXA1蛋白水平在ER+乳腺肿瘤中较低，较低 在假性妇女与无妇女的肿瘤中。支持这一假设，我们最近表明 小鼠乳腺中FOXA1的杂合缺失导致上皮细胞的显着偏斜 人群朝向腔祖先。在这些初步结果的基础上，我们提出了一个全面的 全基因组DNA甲基化分析来自1,621名AA乳腺癌妇女的肿瘤样品来自 黑人妇女的健康研究）和使用Iillumina Epic 850k阵列的女性健康圈。 将这些概况与甲基化后383例AA病例的现有450K数据相结合，我们将 检查区分ER亚组的FOXA1和差异甲基化基因座（DML）。与流行病学 来自这2,004例AA案件的数据，我们将评估生殖风险因素和 使用加权基因相关网络分析和结构方程的FOXA1和顶部DML的甲基化 建模以评估复杂关系。我们将评估平等之间的相同关系， 由健康的AA志愿者捐赠给科门组织的正常乳腺组织中的母乳喂养和甲基化 银行。使用小鼠模型，我们将实验研究平等和母乳喂养是否影响 FOXA1和其他丙泊型候选基因的甲基化水平，以及不同的相对比例 乳腺上皮细胞种群。这种跨学科的多管齐下方法将使我们能够 了解AA女性侵略性乳腺癌的病因，促进新标记的发展 对于那些处于最高风险的人，并揭示了预防预防方法的有希望的分子靶标。