African American (AA) women continue to suffer from high mortality rates from an aggressive form of breast cancer for which there is no treatment. Better understanding of the unique properties of AA tumor cells and the microenvironment that supports its growth might improve clinical outcomes. Macrophages are a lynchpin in tumor microenvironment regulation. Although high macrophage infiltration and increased angiogenesis are unique characteristics of AA breast tumors, mechanisms that support these biological processes remain poorly understood. We have recently demonstrated, for the first time that increase in beige/brown adipose phenotype promote development of xenografts from breast cancer cells. We have subsequently demonstrated that expression of beige markers is significantly increased in both xenografts obtained from AA triple- negative (TN) breast cancer cells as well as in AA TN breast tumors. Based on our published and preliminary data, we hypothesize that ?cross-talk between tumor cells and beige adipocytes generates a unique microenvironment that promotes M2 macrophage phenotype and is conducive to high angiogenesis.? We will test our hypothesis with the following Specific Aims:
Aim 1 : Determine whether i) M2 macrophages increase beige adipose phenotype in breast cancer cells and ii) beige adipose cells crosstalk with tumor cells to increase aggressive behavior in AA TN breast tumors.
Aim 2 : Determine the molecular mechanisms by which beige adipocytes in AA breast tumors support and sustain M2 macrophage population.
Aim 3 : Determine whether Th2 cytokines in AA TN breast tumor microenvironment promote proliferation and commitment of bi-potent adipose precursors (AP) to beige lineage. Effect of depletion of tissue resident macrophages and tyrosine hydroxylase (TH) expressed in these macrophages, on beige adipose phenotype as well as tumor growth in-vivo will be analyzed. Co-culture experiments with adipocytes enriched in beige phenotype and AA TN breast cancer cells will be performed to elucidate mechanisms that support M2 macrophages/angiogenesis. We will examine the possible role of psoriasin, and beige adipose-enriched secretory factors Neuregulin 4 (Nrg4) and Meteorin- like (Metrnl) during the cross-talk between cancer cells and beige adipocytes. We will further analyze the role of psoriasin in promoting MCSC (ALDH+)-induced xenograft growth. Depletion/enrichment of breast tumor cells with adipose precursor PDGFR? cells will be examined for tumor growth, beige adipose/M2 markers and tumor growth. Increased understanding of detailed molecular mechanisms by which beige adipocytes sustain critical threshold of M2 macrophage population in tumor microenvironment and contribute to tumor progression may provide outstanding opportunity for therapeutic intervention for these aggressive AA TN breast tumors.
In this proposal we will examine underlying mechanisms by which, African American (AA) breast tumor cells and beige adipocytes cross-talk to generate a unique tumor microenvironment that promote aggressive tumor behavior. We will also examine breast tumor and adipocyte derived factors that promote the cross-talk between these cell types. Understanding tumor microenvironment will enable us to find novel targets for therapeutic interventions.
