The up-regulation of specific subsets of chemokines/cytokine/ growth factors is often linked to poorer prognosis for women with invasive mammary carcinoma. Chemokines/cytokines/growth factors are important in the recruitment of leukocytes to the tumor microenvironment and for preparation of the pre-metastatic niche which facilitates invasion and metastasis. The rationale for the proposed studies is to determine which receptors are involved in shifting the tumor microenvironment (TME) from one that is non-invasive to one that is invasive, and to determine if we can antagonize those receptor signals at specific time points in tumor progression to prevent or reverse this process. By antagonizing production of chemokines/cytokines by cancer cells (CaCs), cancer associated fibroblasts (CAFs) or cancer associated leukocytes (CALs) at key points in invasion, we will determine the chemokine/chemokine receptor interactions that participate in the cytokine storm that drives inflammation and cancer invasion. We hypothesize that by modulating activation of subsets of chemokine receptors, the TME can be shifted from pro-tumorigenic/pro-invasion to one that is anti-tumorigenic/anti-invasion. There are two specific aims: 1) To determine the contribution made by CAFs and subpopulations of CALs on early mammary tumor progression during the switch to an invasive phenotype and to determine the specific cytokines/chemokine receptors involved in this process. 2) To determine how targeting specific chemokine receptors in all cells versus in leukocytes alone affects invasion of mammary cancer cells in vivo. PUBLIC HEALTH RELEVANCE: We will define the cytokine/chemokine components of the tumor microenvironment (TME) that interact with the inflammatory cells to mediate progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Results from this proposal will reveal chemokine/cytokine/growth factor receptors involved in progression to invasive carcinoma and time points to most effectively target those receptors to mitigate progression to IDC.
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