Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2 gene-amplified breast cancer cells with primary resistance to HER1/2-targeted therapies |
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Authors: | Oliveras-Ferraros Cristina Vazquez-Martin Alejandro Cufí Sílvia Torres-Garcia Violeta Zenobia Sauri-Nadal Tamara Barco Sonia Del Lopez-Bonet Eugeni Brunet Joan Martin-Castillo Begoña Menendez Javier A |
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Institution: | aUnit of Translational Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia, Spain;bGirona Biomedical Research Institute, Avenida de Francia S/N, E-17007 Girona, Catalonia, Spain;cMedical Oncology, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia, Spain;dDepartment of Anatomical Pathology, Dr. Josep Trueta University Hospital, Avenida de Francia S/N, E-17007 Girona, Catalonia, Spain;eUnit of Clinical Research, Catalan Institute of Oncology-Girona, Avenida de Francia S/N, E-17007 Girona, Catalonia, Spain |
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Abstract: | Primary resistance of HER2 gene-amplified breast carcinomas (BC) to HER-targeted therapies can be explained in terms of overactive HER2-independent downstream pro-survival pathways. We here confirm that constitutive overexpression of Inhibitor of Apoptosis (IAP) survivin is indispensable for survival of HER2-positive BC cells with intrinsic cross-resistance to multiple HER1/2 inhibitors. The IC50 values for the HER1/2 Tyrosine Kinase Inhibitors (TKIs) gefitinib, erlotinib and lapatinib were up to 40-fold higher in trastuzumab-unresponsive JIMT-1 cells than in trastuzumab-naïve SKBR3 cells. ELISA-based and immunoblotting assays demonstrated that trastuzumab-refractory JIMT-1 cells constitutively expressed ∼4 times more survivin protein than trastuzumab-responsive SKBR3 cells. In response to trastuzumab, JIMT-1 cells accumulated ∼10 times more survivin than SKBR3 cells. HER1/2 TKIs failed to down-regulate survivin expression in JIMT-1 cells whereas equimolar doses of HER1/HER2 TKIs drastically depleted survivin protein in SKBR3 cells. ELISA-based detection of histone-associated DNA fragments confirmed that trastuzumab-refractory JIMT-1 cells were intrinsically protected against the apoptotic effects of HER1/2 TKIs. Of note, when we knocked-down survivin expression using siRNA and then added trastuzumab, cell proliferation and colony formation were completely suppressed in JIMT-1 cells. Our current findings may be extremely helpful to design successful combinatorial strategies aimed to circumvent the occurrence of de novo resistance to HER2-directed drugs using survivin antagonists. |
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Keywords: | Survivin HER2 Trastuzumab Lapatinib Breast cancer |
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