Using biomarkers to elucidate the breastfeeding and ovarian cancer risk association

摘要 卵巢癌的存活率很低，5年存活率不到50%，而且在 过去几十年。由于缺乏真正可改变的方法，卵巢癌的预防一直具有挑战性 降低卵巢癌风险的因素。母乳喂养与降低卵巢癌风险有关；然而， 关于母乳喂养导致卵巢长期减少的生物途径知之甚少。 癌症风险。该应用程序的目的是阐明母乳喂养和减少 通过确定调节和改变这种关联的因素来增加患卵巢癌的风险。虽然母乳喂养可能会导致 闭经会减少一生中排卵的次数，观察到的保护作用超出了应有的范围 仅由哺乳期闭经所致。我们假设母乳喂养会改变新陈代谢， 局部和全身的炎症和免疫环境，这些变化在以后的几年里一直存在 暴露，导致卵巢癌风险降低。为了研究这些机制，我们将利用现有的 来自两个国际财团的详细问卷数据，包括22项研究(12项)中的854,050名妇女 病例对照研究包括9,357例病例、12,425例对照和包括832,268例在内的10个前瞻性队列 参与者1,900例)，循环炎症和代谢生物标记物数据在 从护士健康研究(NHS/NHSII)的7000多名参与者那里收集样本，以及卵巢 NHS/NHSII中681例卵巢癌患者的肿瘤组织标志物资料及人群调查 英国病例对照研究(NEC)。这一创新项目将利用来自两个国际财团的数据， 使用可重复验证的分析生成的血液生物标记物数据，以及使用切割的组织标记物数据 边缘，多重免疫荧光平台，允许同时考虑多种免疫 记号笔。这些广泛的资源和严谨的方法提供了一个独特的机会来调查 可能有助于解释母乳喂养对降低卵巢癌风险的长期影响的机制。 这个项目的结果将加强我们对潜在的生物途径的理解，通过这些途径 母乳喂养降低了卵巢癌的风险，为卵巢癌预防研究开辟了新的途径。 重要的是，拟议的研究结果有很高的潜力为新的预防策略提供信息。 通过识别关键的炎症、免疫和代谢途径，调节母乳喂养和 因此，极大地改善了被诊断患有这种致命疾病的妇女的结局。

ABSTRACT Ovarian cancer survival is poor with a 5-year survival of less than 50% and has shown little improvement in the past several decades. Prevention of ovarian cancer has been challenging due to the lack of truly modifiable factors that reduce ovarian cancer risk. Breastfeeding is associated with decreased ovarian cancer risk; however, little is known about the biologic pathways impacted by breastfeeding that leads to long-term reduction in ovarian cancer risk. The goal of this application is to elucidate the association between breastfeeding and reduced ovarian cancer risk by identifying factors that mediate and modify this association. While breastfeeding can cause amenorrhea which decreases the lifetime number of ovulations, the observed protection exceeds what would be expected by lactational amenorrhea alone. We hypothesize that breastfeeding alters the metabolic, inflammatory, and immune environment both locally and systemically and these changes persist for years after the exposure, leading to decreased ovarian cancer risk. To examine these mechanisms, we will leverage existing detailed questionnaire data from two international consortia including 854,050 women across 22 studies (12 case-control studies including 9,357 cases, 12,425 controls and 10 prospective cohorts including 832,268 participants with 1,900 cases), circulating inflammatory and metabolic biomarker data measured in prospectively collected samples from more than 7,000 participants in the Nurses’ Health Studies (NHS/NHSII), and ovarian cancer tumor tissue marker data from 681 ovarian cancer cases in NHS/NHSII and the population-based New England Case Control Study (NEC). This innovative project will leverage data from two international consortia, blood biomarker data generated using reproducible validated assays, and tissue marker data using the cutting edge, multiplex immunofluorescence platform that allows simultaneous consideration of multiple immune markers. These extensive resources and rigorous methods provide a unique opportunity to investigate several mechanisms that may help explain the long-term impact of breastfeeding on ovarian cancer risk reduction. Results from this project will enhance our understanding of the underlying biologic pathways through which breastfeeding reduces ovarian cancer risk, opening new avenues for ovarian cancer prevention research. Importantly, findings from the proposed research have high potential to inform novel prevention strategies through identification of key inflammatory, immune, and metabolic pathways modulated by breastfeeding and thus greatly improve outcomes for women diagnosed with this deadly disease.