Project Summary/ Abstract The overarching goal of this project is to examine how socio-structural determinants of health impact the breast tumor DNA methylome, activation of oncogenic signaling and ultimately, the racially disparate development of triple negative breast cancer (TNBC). The etiologic basis of racial disparities in TNBC is not well understood and few studies have investigated the impact of social determinants of health as potential drivers of disparities. Recent work from the McCullough group shows that, in Atlanta, Black women with breast cancer are more likely to live in redlined neighborhoods than White women (80% vs 20%) and that living in areas with high rates of redlining is associated with a 60% increase in breast cancer mortality. These data support the need to investigate redlining as an etiologic driver of race disparities in TNBC. We posit that to achieve health equity, it is necessary to understand how socio-structural inequities can be adversely manifested biologically, resulting in breast cancer. The goal of this study is to elucidate a biological mechanism that explains the association between neighborhood-level redlining and disparities in TNBC. This investigation requires a researcher with a diverse skillset that can address questions from the population to the bench. This Pathway to Independence Award (K99/R00) application by Dr. Miller-Kleinhenz intends to uniquely position her to answer these questions by building on her prior expertise in breast tumor biology and expanding her skill set in social and molecular epidemiology and epigenetics. To achieve the aims of this research, Dr. Miller-Kleinhenz will focus her training in three areas, (1) increasing knowledge through a comprehensive didactic curriculum, (2) experiencing and learning from varied research environments, and (3) fostering professional development through leadership, scientific communication, and then transitioning to independence. These training goals will be supervised by an interdisciplinary mentoring team, led by Dr. Lauren McCullough, a cancer health disparities and molecular epidemiology expert and an Assistant Professor of Epidemiology at Rollins School of Public Health at Emory University. The co-mentor will be Dr. Adam Marcus, an expert cancer biologist and a Professor of Hematology and Oncology and the Interim Executive Director of the Winship Cancer Institute. This training will aid Dr. Miller-Kleinhenz to pursue the following aims during the K99 phase: Understanding the impact of redlining as a social-structural determinant of health that is associated with TNBC development (Aim 1) and examining redlining-associated DNA methylation signatures of the breast tumor epigenome in TNBC (Aim 2). During the R00 phase, she will determine the pathobiological significance of redlining-associated expression of oncogenic signaling pathways in TNBC (Aim 3). This 5-year research and training plan will allow Dr. Miller-Kleinhenz to establish an independent research program that will elucidate new avenues for policy interventions and pharmacological treatments that would contribute to the ultimate goal of reducing cancer health disparities.

Project Narrative Triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, affects about 20% of breast cancer patients and is disproportionately diagnosed in young, Black women. Researching how socio-structural determinants of health “above the skin” influence biological mechanisms “under the skin” could help to understand potential drivers of racial disparities in TNBC. This study focuses on how neighborhood-level redlining contributes to disparities in TNBC incidence through epigenetic changes and activation of oncogenic signaling pathways, leading to tumorigenesis.