Social Genomic Mechanisms Linking Structural Racism, Perceived Discrimination, and Breast Cancer Survival - PROJECT SUMMARY Women living in historically redlined neighborhoods impacted by structural racism and discrimination (SRD) have shorter breast cancer (BCa) recurrence-free survival (RFS) compared to women living in non-historically redlined neighborhoods. This disparity persists after controlling for individual, behavior, lifestyle, environmental, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics, suggesting unaccounted mechanisms by which SRD impact BCa RFS. Our preliminary data indicate that SRD, through neural influences on BCa biology, may shorten BCa RFS. Specifically, we leveraged the novel genomic-epidemiologic infrastructure of our Miami Breast Cancer Disparities study, a prospective cohort study with clinically and survey-annotated blood and tissue samples, to discover that both objective SRD [defined using the Index of Concentration at the Extremes (ICE)] and subjective perceived discrimination [PD, defined using the using the Expanded Everyday Discrimination Scale Survey (EEDS)] are independent predictors of 1) higher levels of myeloid lineage immune cell activation in blood (a pattern known as the Conserved Transcriptional Response to Adversity; CTRA) and 2) a more aggressive BCa molecular biology profile (up-regulation of proinflammatory transcription factors (TF) NF-kB and AP-1), after controlling for individual (e.g., age, race/ethnicity, behavior, lifestyle, comorbidities), environmental (e.g., air pollution), tumor (e.g., stage, subtype), and treatment (e.g., neoadjuvant chemotherapy) factors. In addition, this aggressive BCa molecular biology profile correlated with shorter RFS. We also discovered that both SRD and PD are associated with up-regulation of TF CREB (a marker of SNS activity), implicating the SNS as a potential mediator of SRD and shorter RFS through pro-inflammatory NF-kB and AP-1 regulation. Combined, our preliminary data provide strong evidence for our central hypothesis that SRD and PD are associated with shorter RFS, in part, through biologic mechanisms mediated by SNS regulation (CREB) of circulating myeloid lineage immune cells (CTRA) resulting in an aggressive tumor biology molecular profile. To test our central hypothesis, we propose the following aims in the largest social genomics BCa study to date, consisting of 750 diverse (∼18% non-Hispanic White, 24% non-Hispanic Black, and 58% Hispanic) BCa patients enrolled in our MBCD study: Aim 1) Define the contributions of objective SRD and subjective PD on BCa RFS. Aim 2) Validate the biologic mechanisms mediating the effects of SRD on RFS. Aim 3) Evaluate the spatial effects of clinical and biologic correlates of shorter RFS. Combined, these findings, to our knowledge, will represent the single largest social genomics and geospatial BCa research effort to study BCa RFS disparities with an innovative focus on 1) isolating the distinct biologic mechanisms associated with SRD (ICE) and PD (EEDS) and RFS, and 2) geospatial identification of at-risk neighborhoods defined as having more SRD, aggressive biology, and shorter RFS to inform future policy and targeted behavioral or therapeutic to deduce SNS activity to adversity and thus based on prior randomized control trials, reverse aggressive tumor biology, ultimately improving BCa RFS for high-risk marginalized populations.
