Given the role of the CXCR4/CXCL12 axis in breast cancer metastatic spread, and the differences observed between MDA-MB-231 and MCF-7 cells, our data point to initial stages of breast cancer as possible models where targeting the CXCL12/HMGB1 heterocomplex could be particularly promising. Here, HMGB1 is linked to breast carcinoma.