Gamma-irradiation induces HER-2/neu overexpression in breast cancer cell lines and sensitivity to treatment with trastuzumab

• Published in: International journal of radiation biology 2013-05, Vol.89 (5), p.319-325
• Main Authors: Voutsas, Ioannis F., Mahaira, Louisa G., Fotopoulou, Katerina, Kapranos, Nikiforos, Reclos, John G., Gritzapis, Angelos D., Papamichail, Michail, Perez, Sonia A., Baxevanis, Constantin N.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; cellular radiobiology; Chromosome Aberrations - drug effects; Chromosome Aberrations - radiation effects; Chromosomes, Human, Pair 17 - drug effects; Chromosomes, Human, Pair 17 - genetics; Chromosomes, Human, Pair 17 - radiation effects; Combined Modality Therapy - methods; Drug Resistance, Neoplasm - radiation effects; Gamma Rays - therapeutic use; Gamma-irradiation; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - radiation effects; HER-2/neu; Humans; In Situ Hybridization, Fluorescence; Receptor, ErbB-2 - metabolism; Space life sciences; Trastuzumab
• ISSN: 0955-3002; 1362-3095
• DOI: 10.3109/09553002.2013.765617

Abstract Purpose: Overexpression of human epidermal growth factor receptor-2 (HER-2/neu) in breast cancer patients is a prerequisite for treatment with trastuzumab. In the present study, we demonstrate by fluorescence in situ hybridization (FISH) analysis that HER-2/neu gene amplification and chromosome 17 (CEP17) polysomy can be induced by irradiation in human breast cancer cell lines with low basal level of HER-2/neu. Materials and methods: The irradiation-induced HER-2/neu gene amplification and CEP17 polysomy enhanced HER-2/neu at the protein level in both human MDA-MB-231 and MDA-MB-435 breast cancer cell lines which was determined by immunohistochemistry and fluorescence analysis and was correlated with mRNA levels. Results: Irradiation affected to a high degree the responsiveness of both cell lines to in vitro treatment with trastuzumab. The direct antiproliferative effect of trastuzumab, as well as its capacity to induce natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), was considerably higher in the irradiated tumor cells compared to their non-irradiated counterparts. Conclusion: Our data demonstrate that irradiation induces HER-2/neu gene amplification and CEP17 polysomy thereby enhancing expression of this protein in breast cancer cell lines rendering them susceptible to treatment with trastuzumab. They also suggest that patients with HER-2/neu negative inoperable tumors undergoing local radiation therapy may benefit from treatment with trastuzumab.