Social genomic mechanisms linking geographic location to breast cancer survival - Recent studies have discovered that where one lives is associated shorter or longer breast cancer (BCa) recurrence-free survival (RFS) independent of individual, behavior, lifestyle, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics, suggesting unaccounted mechanisms by which one’s geographic location impacts BCa RFS. Our preliminary data indicate that geographic location, through neural influences on BCa biology, may lead to shorter or longer BCa RFS. Specifically, we leveraged the novel genomic-epidemiologic infrastructure of our Miami Breast Cancer Cohort study, a prospective cohort study with clinically and survey-annotated blood and tissue samples, to discover that positive and negative factors associated with where one lives and positive and negative perceptions of where one lives are independent predictors of 1) lower or higher levels of myeloid lineage immune cell activation in blood (a pattern known as the Conserved Transcriptional Response to Adversity; CTRA) and 2) a less or more aggressive BCa molecular biology profile (up-regulation of proinflammatory transcription factors (TF) NF-kB and AP-1), respectively, after controlling for individual, tumor, and guideline-concordant treatment factors. In addition, an aggressive BCa molecular biology profile correlated with shorter RFS. We also discovered that where one lives and one’s perceptions of where he or she lives, are associated with up- or down-regulation of TF CREB [a marker of sympathetic nervous system (SNS) activity], implicating the SNS as a potential mediator of geographic location and RFS through NF-kB and AP-1 regulation. Combined, our preliminary data provide strong evidence for our central hypothesis that where one lives and one’s perceptions of where he or she lives are associated with RFS, in part, through biologic mechanisms mediated by SNS regulation (CREB) of circulating myeloid lineage immune cells (CTRA) resulting in a more or less 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 BCa patients enrolled in our study: Aim 1) Define the contributions of where one lives (geographic location) and one’s perception of where he or she lives on BCa RFS. Aim 2) Validate the biologic mechanisms mediating the effects of geographic location 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 how geographic location influences BCa RFS with an innovative focus on 1) isolating the distinct biologic mechanisms associated with where one lives, one’s perceptions of where he or she lives, and RFS, and 2) geospatial identification of areas with less aggressive biology and longer RFS to inform future policy and targeted behavioral or therapeutic interventions to reduce SNS activity and thus based on prior randomized control trials, reverse aggressive tumor biology, ultimately improving BCa RFS.
