Project Summary The long-term objective of this project is to develop Dr. Romanos-Nanclares’s capacity to conduct studies that integrate dietary and lifestyle factors with multi-omics data and traditional biomarkers to better understand the biological pathways underlying the etiology of aggressive forms of breast cancer and to advance the field of precision nutrition for cancer prevention. The proposed research combines ‘omics methodologies with advanced statistical techniques to investigate the role of chronic inflammation in the etiology of breast cancer. Chronic inflammation has been identified as a possible risk factor in the development of breast cancer, including estrogen receptor negative breast cancer, which is a subtype of breast cancer that is associated with poorer prognosis and is less responsive to hormonal therapies. The foundation for this proposal is based on our recent findings where a higher adherence to an Empirical Dietary Inflammatory Pattern (EDIP) score (or a more pro- inflammatory diet) was associated with increased breast cancer risk, particularly for tumors lacking estrogen receptor expression. Leveraging the unique design and wealth of resources in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII), with repeated dietary measures and prediagnostic plasma specimens, this application will combine dietary and ‘omics data from multiple biological dimensions with cutting-edge epidemiological and bioinformatics methodologies to examine the relationship between chronic inflammation and invasive breast cancer risk and estrogen receptor subtypes. In Aim 1 (K99), she will examine the associations of plasma metabolomic profiles of EDIP with subsequent risk of breast cancer in the NHS and NHSII among 1,997 cases and their matched controls. In Aim 2 (R00), she will use an agnostic approach to identify the associations of plasma proteomics with risk of breast cancer in the NHS and NHSII among 200 cases and their matched controls. In Aim 3 (R00), she will integrate multi-omics data, including metabolomics, proteomics, and transcriptomics, to characterize the role of inflammation in breast cancer etiology. This research will provide novel evidence, enhance our understanding of the biological mechanisms involved in breast cancer etiology, and help identify new prevention strategies for more aggressive forms of the disease. Dr. Romanos-Nanclares’s scientific aims are supported by three training objectives that will allow her to advance her trajectory toward becoming an independent investigator: 1) single-omics and multi-omics methodologies and advanced analytics; 2) proteomics study design and execution; and 3) breast cancer etiology and pathophysiology. The training environment at Brigham and Women’s Hospital will provide exceptional support for Dr. Romanos-Nanclares as she pursues these development and scientific goals. She has assembled an outstanding interdisciplinary mentoring team with expertise in cancer epidemiology, multi-omics bioinformatics, breast cancer pathology, proteomics, and metabolomics. This K99/R00 award will help Dr. Romanos-Nanclares acquire the knowledge and experience necessary to launch her career as an independent investigator.

Project Narrative This Pathway to Independence Award will apply a multi-omics approach, building on the unique design and rich dietary and biomarker data in the Nurses’ Health Studies to comprehensively evaluate the relationship between chronic inflammation and breast cancer risk. The proposed research project will provide novel insight into inflammatory pathways and specific proteins that will serve as the critical first steps for future development of risk biomarkers and therapeutic targets for preventing ER-negative breast cancer. The project also has the potential to inform more effective and precision dietary approaches for the prevention of breast cancer, and particularly aggressive breast tumor subtypes.