Abstract
Tumor heterogeneity may broadly influence the activation of tumor-associated macrophages. We aimed to dissect how breast cancer cells of different molecular characteristics contribute to macrophage phenotype and function. Therefore, we performed whole transcriptome sequencing of human monocytes that were co-cultured with estrogen receptor positive (ER(+)) or triple-negative (TNBC) breast cancer cell lines and studied the biological responses related to the differential gene activation in both monocytes and cancer cells by pathway analysis. ER(+) and TNBC cancer cell lines induced distinctly different macrophage phenotypes with different biological functions, cytokine and chemokine secretion, and morphology. Conversely, ER(+) and TNBC breast cancer cell lines were distinctly influenced by the presence of macrophages. ER(+) cells demonstrated up-regulation of an acute phase inflammatory response, IL-17 signaling and antigen presentation pathway, whereas thioredoxin and vitamin D3 receptor pathways were down-regulated in the respective macrophages. The TNBC educated macrophages down-regulated citrulline metabolism and differentiated into M2-like macrophages with increased MMR protein expression and CCL2 secretion. These data demonstrate how different cancer cells educate the host cells to support tumor growth and might explain why high infiltration of macrophages in TNBC tumors associates with poor prognosis.