ABSTRACT
BACKGROUND: Recently, interferon-inducible guanylate binding protein (GBP2) has been discussed as a possible control factor in tumor development, which is controlled by p53, and inhibits NF-Kappa B and Rac protein as well as expression of matrix metalloproteinase 9. However, the potential role that GBP2 plays in tumor development and prognosis has not yet been studied. METHODS: We analyzed whether GBP2 mRNA levels are associated with metastasis-free interval in 766 patients with node negative breast carcinomas who did not receive systemic chemotherapy. Furthermore, response to anthracycline-based chemotherapy was studied in 768 breast cancer patients. RESULTS: High expression of GBP2 in breast carcinomas was associated with better prognosis in the univariate (P < 0.001, hazard ratio 0.763, 95 % CI 0.650-0.896) as well as in the multivariate Cox analysis (P = 0.008, hazard ratio 0.731, 95 % CI 0.580-0.920) adjusted to the established clinical factors age, pT stage, grading, hormone and ERBB2 receptor status. The association was particularly strong in subgroups with high proliferation and positive estrogen receptor status but did not reach significance in carcinomas with low expression of proliferation associated genes. Besides its prognostic capacity, GBP2 also predicted pathologically complete response to anthracycline-based chemotherapy (P = 0.0037, odds ratio 1.39, 95 % CI 1.11-1.74). Interestingly, GBP2 correlated with a recently established T cell signature, indicating tumor infiltration with T cells (R = 0.607, P < 0.001). CONCLUSION: GBP2 is associated with better prognosis in fast proliferating tumors and probably represents a marker of an efficient T cell response.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , GTP-Binding Proteins/genetics , T-Lymphocytes/immunology , Biomarkers, Tumor/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Cohort Studies , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Immunoenzyme Techniques , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Survival RateABSTRACT
Nanoparticles (NP) as carriers for anti-cancer drugs have shown great promise. Specific targeting of NP to malignant cells, however, remains an unsolved problem. Conjugation of antibodies specific for tumor membrane antigens to NP represents one approach to improve specificity and to increase therapeutic efficacy. In the present study, for the first time a novel membrane heat shock protein (Hsp70)-specific antibody (cmHsp70.1) was coupled to human serum albumin (HSA) NP, loaded with microRNA (miRNA) plasmids to target the inhibitor of apoptosis protein survivin. The physicochemical properties of monodisperse miRNA-loaded NP showed a diameter of 180 nm to 220 nm, a plasmid incorporation of more than 95% and a surface binding capacity of the antibody of 70-80%. Antibody-conjugated NP displayed an increased cellular uptake in U87MG and LN229 glioblastoma cells compared to isotype control antibody, PEG-coupled controls and peripheral blood lymphocytes (PBL). Survivin expression was significantly reduced in cells treated with the Hsp70-miRNA-NP as compared to non-conjugated NP. Hsp70-miRNA-NP enhanced radiation-induced increase in caspase 3/7 activity and decrease in clonogenic cell survival. In summary, cmHsp70.1 miRNA-NP comprise an enhanced tumor cell uptake and increased therapeutic efficacy of radiation therapy in vitro and provide the basis for the development of antibody-based advanced carrier systems for a tumor cell specific targeting.
