Using biomarkers to elucidate the breastfeeding and ovarian cancer risk association

摘要 卵巢癌的生存率很低，5年生存率低于50%，并且在治疗后几乎没有改善。 过去几十年。卵巢癌的预防一直具有挑战性，因为缺乏真正的可改变的 降低卵巢癌风险的因素。母乳喂养与卵巢癌风险降低有关;然而， 关于母乳喂养影响的导致卵巢功能长期下降的生物学途径知之甚少， 癌症风险。本申请的目的是阐明母乳喂养与减少 卵巢癌的风险，通过识别介导和修改这种关联的因素。母乳喂养会导致 闭经，减少排卵的终身数量，观察到的保护超过了 仅由哺乳期闭经引起。我们假设母乳喂养改变了新陈代谢， 炎症和免疫环境，这些变化持续多年后， 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项研究中的854，050名女性（12 病例对照研究包括9，357例病例，12，425例对照和10个前瞻性队列，包括832，268例 参与者1，900例），前瞻性测量循环炎症和代谢生物标志物数据， 收集了7,000多名护士健康研究（NHS/NHSII）参与者的样本， 来自NHS/NHSII中681例卵巢癌病例的癌症肿瘤组织标志物数据和基于人群的新 英国病例对照研究（NEC）。这一创新项目将利用两个国际财团的数据， 使用可再现的经验证的测定生成的血液生物标志物数据，以及使用切割的组织标志物数据 边缘，多重免疫荧光平台，允许同时考虑多种免疫 标记。这些广泛的资源和严格的方法提供了一个独特的机会，调查几个 这些机制可能有助于解释母乳喂养对降低卵巢癌风险的长期影响。 该项目的结果将增强我们对潜在生物学途径的理解， 母乳喂养可降低卵巢癌风险，为卵巢癌预防研究开辟了新途径。 重要的是，拟议研究的结果很有可能为新的预防策略提供信息。 通过识别母乳喂养调节的关键炎症、免疫和代谢途径， 从而大大改善被诊断患有这种致命疾病的妇女的结果。

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.