DESCRIPTION (provided by applicant): African American (AA) women are more likely to have aggressive breast cancer (BC) and experience greater mortality rates as compared to Caucasian (CA) women. Another upsetting fact is that this cancer outcome gap has continued to widen over past several years underscoring the immediate need to make progress in this area. It is being increasingly appreciated that tumor microenvironment (TME) may play an important role in BC racial disparity; however, underlying molecular and mechanistic basis is not clearly understood. This project is built upon our novel findings suggesting the existence of a TME-tumor cell interaction-driven regulatory loop, which is predominantly active in AA patients. We demonstrate that 1) serum levels of inflammatory cytokines, resistin and IL6, are significantly elevated in AA BC patients compared to their CA counterparts, 2) AA BCs have significantly greater expression and phosphorylation of STAT3 compared to CA BCs, 3) treatment of triple-negative breast cancer (TNBC) cell lines from both AA and CA patients with resistin promotes expression of STAT3/pSTAT3 and enhances IL6 production, thus suggesting a dominant role of differential TME in overall disease outcome, 4) IL6 mediates the effect of resistin on STAT3 phosphorylation, 5) resistin promotes aggressive tumor phenotypes and therapy-resistance in BC cells through STAT3 induction, 6) resistin also upregulates LIN28A, a regulator of stemness, and downregulates let-7 miRNA, and 7) LIN28A silencing abrogates resistin-induced upregulation of IL6, pSTAT3 and STAT3. Based on these findings, we hypothesize that intrinsic differences in tumor biology contributes to BC racial disparity and resistin-LIN28A-(IL6)- STAT3/pSTAT3 serves as an important regulatory loop controlling the aggressive and therapy-resistant phenotypes of BC cells. This hypothesis will be tested in three specific aims. In aim 1, we will characterize the molecular mechanisms underlying resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop by examining the pathways regulating resistin-induced LIN28A expression, and whether LIN28A mediates resistin-induced let-7 downregulation, which then leads to STAT3 and IL6 upregulation in BC cells. In aim 2, we will examine the functional significance of this regulatory by using luciferase-tagged, control or LIN28A-/STAT3-silenced BC cell lines and characterize the response of resistin and its downstream effectors on growth, metastasis and therapy-resistance in an orthotopic nude mice model. In aim 3, we will determine the clinical relevance of the components of resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop in BC racial disparity by examining their expression in clinical samples and assessing their correlation (alone and in combination) with TME and tumor cell characteristics as well as with race and patient's survival. Together, these studies will provide novel insight into molecular causes and mechanistic underpinning of BC rac...