Identifying the role of the gut microbiome in the etiology of benign breast disease

项目摘要/摘要 这个项目的总体目标是确定肠道微生物群在良性乳腺疾病病因学中的作用。 (BBD)，从而阐明其与乳腺癌相关的发病机制。大约每隔一分钟就有一人 美国有五名女性被诊断出患有BBD，这是一种公认的乳腺癌风险指标。 BBD与乳腺癌具有与荷尔蒙相关的危险因素。然而，潜在的链接机制 激素因素与乳腺疾病的关系尚不清楚。新出现的证据表明，肠道微生物群可能是 明显参与乳腺疾病，通过影响全身雌激素动态平衡。这一证据 支持肠道微生物群在乳房疾病中起关键作用的假设，它可能介导 激素危险因素与BBD的关系。然而，没有一项研究系统地研究了 BBD的肠道微生物群及其代谢物。王博士建议第一个测试这一重要的 假设。她将利用护士健康研究II中嵌入的子研究，以 测试这三个具体目标。在目标1(K99)中，她将确定肠道微生物组成的潜在差异 以及各种激素因素在约1800名参与者中的功能变化。在《目标2》(R00)中，她将 描述肠道微生物组组成与高危、增殖性肺炎亚型之间的关系 BBD采用嵌套式病例对照研究(N=300)，采集乳房活检样本。在《目标3》(R00)中，她将 结合肠道微生物组的功能读数，粪便代谢组学，来评估两者之间的联系 同一嵌套病例对照研究中微生物代谢特征与BBD之间的关系。创新的猎枪 元基因组测序和半靶向代谢组学将用于发现微生物菌株和它们的 代谢物。通过整合元基因组学和代谢组学，她将全面研究分类学 与BBD直接相关的肠道微生物群落的组成和功能潜力 肠道微生物群在激素因素-BBD关联中的潜在中介作用。结果 可能为新的个性化BBD和乳腺癌的预防铺平道路。 风险女性由她们的荷尔蒙特征和肠道微生物群的潜在调节来定义。王医生的 研究目标得到了针对她的两个培训目标量身定做的全面培训计划的支持：1)获得培训 并将先进的生物信息学分析应用于大型微生物组元基因组和代谢组学数据集；以及 2)发展有关BBD流行病学、病因学、病理学和 发病机制，因为它与乳腺癌有关。布里格姆妇女医院的培训环境促进了 生产力和与世界级生物医学科学家的合作，她已经组建了一个多学科的 指导团队，包括BBD、人类微生物组、生物信息学、激素因素、 乳房病理学和乳腺癌流行病学。这个K99/R00奖将帮助她获得知识和 作为一名独立的乳腺癌调查员，她有必要的经验来有效地从事她的职业生涯。

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to identify the role of the gut microbiome in the etiology of benign breast disease (BBD), and thereby shed light on its pathogenesis in relation to breast cancer. Approximately one out of every five women in the United States has been diagnosed with BBD, a well-established risk indicator for breast cancer. BBD share the hormonal-related risk factors with breast cancer. However, the underlying mechanisms linking hormone factors and breast disease are not clear. Emerging evidence suggests that the gut microbiome may be significantly involved in breast disease through the influence on systemic estrogen homeostasis. This evidence supports the hypothesis that the gut microbiome is a key player in breast disease, and it may mediate the associations between hormonal risk factors and BBD. However, no study has systematically studied the role of the gut microbiome and its metabolome on BBD. Dr. Wang proposes to be the first to test this important hypothesis. She will leverage the sub-studies embedded in the well-characterized Nurses’ Health Study II, to test the three specific aims. In Aim 1 (K99), she will identify potential differences in gut microbial composition and functional variation by various hormonal factors among ~1800 participants. In Aim 2 (R00), she will characterize the associations between gut microbiome composition and the high-risk, proliferative subtype of BBD in a nested case-control study (N=300) with breast biopsy sample collection. In Aim 3 (R00), she will incorporate the functional readout of gut microbiome, the fecal metabolomics, to estimate the associations between microbial metabolomic signatures and BBD in the same nested case-control study. Innovative shotgun metagenomic sequencing and semi-targeted metabolomics will be used to discover microbial strains and their metabolites. By integrating metagenomics and metabolomics, she will comprehensively investigate taxonomic composition and functional potential of gut microbial communities that are directly involved in BBD, as well as the potential mediating role of the gut microbiome underlying the hormonal factors-BBD associations. Results from the proposed study may pave the way for novel personalized BBD and breast cancer prevention for high- risk women defined by their hormonal profiles, with the potential modulation of gut microbiome. Dr. Wang’s research aims are supported by a well-rounded training plan tailored to her two training goals: 1) Obtain training and apply advanced bioinformatic analytics to large microbiome metagenomic and metabolomics datasets; and 2) Develop advanced knowledge on hormonal determinants on BBD epidemiology, etiology, pathology, and pathogenesis as it relates to breast cancer. The training environment at Brigham and Women’s Hospital fosters productivity and collaboration with world class biomedical scientists, and she have assembled a multidisciplinary mentoring team that includes leading experts in BBD, human microbiome, bioinformatics, hormonal factors, breast pathology, and breast cancer epidemiology. This K99/R00 award will help her gain the knowledge and experience necessary to effectively pursue her career as an independent breast cancer investigator.