Journal
ONCOLOGY LETTERS
Volume 13, Issue 6, Pages 4224-4230Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ol.2017.5994
Keywords
breast cancer; cathepsin B; CXCR3; CTSB; survival; CXCL9; CXCL10
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Funding
- Wilhelm Sander-Stiftung [2011.006.1, 2011.006.2]
- Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences component of the National Institutes of Health [KL2TR000440]
- NIH roadmap for Medical Research
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Cathepsin B (CTSB) is a lysosomal cysteine protease that has been linked to the progression of breast cancer, for example by activation of other proteases and tumor-promoting cytokines, thereby supporting tumor invasion and metastasis. Previously, it was shown that CTSB cleaves and inactivates C-X-C motif chemokine receptor 3 (CXCR3) chemokines. As CXCR3 ligands have been demonstrated to induce proteases in cancer cells, the present study hypothesized that they may also affect CTSB in breast cancer cells. The results demonstrated that the human breast cancer tumor cell lines MCF-7 and MDA-MB-231 express the CXCR3 splice variants A and B and CTSB. Upon binding to CXCR3, the two chemokine ligands C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 trigger upregulation of CTSB in these breast cancer cells, whereas the CXCR3-B-specific ligand CXCL4 has no such effect, suggesting the involvement of CXCR3-A in the regulation of CTSB. In early-stage human breast cancer specimens (n=81), overexpression of CXCR3 is associated with statistically significant poorer overall survival, independent of lymph node status, tumor size and nuclear grading (hazard ratio=1.99; 95% confidence interval=1.00-3.97; P=0.050). In conclusion, the data from the current study propose a so far unknown mechanism by which breast cancer cells may exploit tumor-suppressive chemokines to enhance their invasiveness and reduce immune cell infiltration by the degradation of these chemokines. This mechanism may support the established unfavorable prognostic feature of CXCR3 expression in breast cancer.
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