Using biomarkers to elucidate the breastfeeding and ovarian cancer risk association

摘要

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.