Although the pathways activated by extracellular HMGB1-RAGE interaction in breast cancer cells have not been identified, this study showed that rHMGB1 induced the phosphorylation of AKT, ERK, mTOR, and S6 in MDA-MB-231 P. Only p-AKT but not p-ERK, however, was activated in MCF-7 after rHMGB1 treatment. This evidence concerns the gene HMGB1 and breast cancer.