Figure 1. Breast cancer survival network. Chemotherapy results in a burst of paracrine factors near breast tumors that upregulate survival pathways in the cancer cells, causing chemotherapeutic resistance and metastasis. The process begins when chemotherapy induces the release of tumor necrosis factor-a (TNF-a) [a] from stromal cells in the breast, including endothelial cells. As a result, chemokine CXC motif ligand 1 (CXCL1; GRO; MGSA) and CXCL2 (MIP2) are upregulated in breast cancer cells [b] by mechanisms including TNF-a release. The release of CXCL1 and CXCL2 attracts CXC chemokine receptor 2 (CXCR2; IL8RB)-expressing stromal cells from the tumor microenvironment to the tumor. Specifically, CXCR2-expressing, complement receptor 3 (CR3; CD11b)+/lymphocyte antigen 6 complex locus G (LY6G; GR1)+ myeloid cells accumulate near the tumor [c]. The myeloid cells release paracrine factors including S100 calcium binding protein A8 (S100A8; calgranulin A; MRP8) and S100A9 (calgranulin B; MRP14) [d], which activate kinases such as MAP kinase 3 (MAPK3; ERK-1), MAPK1 (ERK-2), MAPK and ribosomal protein S6 kinase 70 kDa polypeptide 1 (RPS6KB1; S6K1) on the breast cancer cells [e]. Activation of the cancer-associated kinases promotes cancer cell survival and metastasis.

CXCR2 antagonists prevent CXCR2-expressing myeloid cells from homing to cancer cells, blocking release of S100A8 and S100A9 and subsequent kinase signaling that promotes cancer survival. Blocking CXCR2 could reduce chemotherapy resistance and breast cancer metastasis.