Using functional proteomics analysis, we examined CXCR4 protein expression in 184 fresh-frozen breast tumor tissues, including 34 HER2+, from breast cancer patients with or without chemotherapy and/or trastuzumab treatment, consistent with our findings from the cell lines, comparing the primary tumors, CXCR4 expression significantly increased in the residual tumor tissues, suggesting that CXCR4 can be a biomarker to predict the drug resistance. Here, CXCR4 is linked to breast cancer.