Raman, Dayanidhi; Howqrd, Cory M.; Sridharan, Sangita; Tilley, Augustus M.C.
CXCR4 is a Gi
-coupled chemokine receptor involved in chemotaxis (directed migration) of tumor and stromal cells into the primary tumor and the pro-metastatic niche that are enriched in CXCL12. In breast cancer, cell surface CXCR4 levels and activity are upregulated and play an important role in local invasion and metastasis. During cancer progression, the CXCL12-CXCR4 axis orchestrates infiltration of endothelial cells and a variety of leukocytes to drive an immunosuppressive tumor microenvironment (TME). When CXCL12 from the TME activates plasma membrane-resident CXCR4 in tumor and stromal cells, a variety of pathways are activated involving signaling modules such as PI3K-AKT, MEK-ERK, and c-Src-p130CAS-paxillin. This triggers a wide variety of cellular processes that
drives breast cancer progression, chemoresistance, and metastasis. This provides an opportunity to intervene and target these signaling axes or nodes in clinical trials to antagonize tumor growth metastasis. Finally, careful selection of targeted therapies in combination with the standard of care therapy should be selected judiciously for each patient (precision medicine) with the aim of improving the longevity with minimal toxicity to metastatic breast cancer patients.