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 racial disparity and provide novel set of biomarkers and potential drug-targets to develop novel ways for reducing the widening gaps in clinical outcome of AA and CA BC patients.
Cancer health disparities represent a major public health concern in the United States and there is a clear perception that these disparities exist at the molecular level and tumor microenvironment (TME) plays an important role. The proposed research will characterize TME-tumor cell interaction-driven molecular cross-talk and confirm its functional and clinical relevance in racially-disparate clinical outcomes of breast cancer (aggressiveness and therapeutic-resistance) between Caucasian (CA) and American (AA) patients. Anticipated findings will be helpful in understanding the molecular and mechanistic basis of breast cancer racial disparity, reveal therapeutically-significant intervention points and identify a novel set of mechanistically-linked biomarkers to serve as risk-predictors and molecular sub-classifiers of disease and thus ultimately be helpful in reducing the observed cancer outcome gaps.
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| Deshmukh, Sachin Kumar; Srivastava, Sanjeev K; Tyagi, Nikhil et al. (2017) Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings. Carcinogenesis 38:757-765 |
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| Zubair, Haseeb; Azim, Shafquat; Srivastava, Sanjeev Kumar et al. (2016) Glucose Metabolism Reprogrammed by Overexpression of IKK? Promotes Pancreatic Tumor Growth. Cancer Res 76:7254-7264 |
