HBXIP Reduces Radiosensitivity Of Human Breast Cancer Cells

Objective:Hepatitis B X-interacting protein (HBXIP) plays an important role in breast tumorigenesis, tumor growth and metastasis. In the present study, we report that activation of HBXIP leads to radiation resistance in breast cancer cells via upregulated XIAP signaling.Methods:Gain-or loss-of HBXIP function was achieved in MDA-MB-231 and MCF-7 cells by transfecting pCMV-HBXIP overexpressing vectors and si-RNA for silencing HBXIP. Breast cancer cell proliferation and growth were determined with MTT and colony forming assays. Cellular apoptosis was determined with flow cytometry. Expression of HBXIP protein and mRNA was determined by Western blotting and RT-PCR. In vivo, we determined the role of HBXIP in radioresistance using xenograft model in athymic nude mice.Results:HBXIP expression was significantly induced in radioresistant breast cancer cell lines. Breast cancer cells with upregulated HBXIP expression showed significantly less radiation-induced apoptosis. Intriguingly, si-RNA-mediated depletion of NF-κB or XIAP sensitized cells, which overexpressed HBXIP, to irradiation, suggesting that the HBXIP-NF-κB-XIAP axis regulates radioresistance of breast cancer cell lines. Breast cancer cells with si-RNA-mediated depletion of NF-κB or XIAP showed markedly more radiation-induced apoptosis. Furthermore, NF-κB and XIAP expression was also significantly induced in radioresistant breast cancer cell lines. In vivo, HBXIP overexpression enhanced the radioresistance of xenograft tumors developed from wild type breast cancer cells by upregulating XIAP expression.Conclusions:Our results suggest that HBXIP enhances radioresistance of human breast cancer cells via upregulating XIAP. Thus, targeting the HBXIP-NF-κB-XIAP pathway is a potentially effective strategy to enhance the efficacy of radiotherapy for human breast cancer.