Producción CyT
Congreso
Autoría
Tapia, Ivana
;
Perico, Davide
;
De Palma, Antonella
;
Wolos, Virginia J
;
VILLAVERDE, MARCELA SOLANGE
;
Mauri, Pier L
;
Rocca,
;
Abrigo, M
;
Silvestre,
;
Fiszman G.L
Fecha
2022
Editorial y Lugar de Edición
scielo
Resumen
Información suministrada por el agente en
SIGEVA
Breast cancer (BC) is the leading cause of death in women worldwide. Around 15-20% of BC tumors overexpress HER2, which is associated with poor disease-free survival. Targeted anti-HER2 therapies such as Trastuzumab (Tz), provide an option for these patients. However, ~60% of them acquire a resistant phenotype during the first year of treatment. In order to identify protein profiles associated with Tz resistance, a comparative proteomic study was performed. Two differential Tz response levels i...
Breast cancer (BC) is the leading cause of death in women worldwide. Around 15-20% of BC tumors overexpress HER2, which is associated with poor disease-free survival. Targeted anti-HER2 therapies such as Trastuzumab (Tz), provide an option for these patients. However, ~60% of them acquire a resistant phenotype during the first year of treatment. In order to identify protein profiles associated with Tz resistance, a comparative proteomic study was performed. Two differential Tz response levels in a 3D culture model were mimicked using a HER2+ human mammary adenocarcinoma cell line (BT-474) and its derived resistant cell line developed in our laboratory (partial Responder Spheroids RS and non-Responder Spheroids n-RS, respectively). For 15 days both spheroids were treated with Tz (50 𝛍g/ml) (%inhibition, RS: 51.2±11.1 and n-RS: 23.1±6.3; ANOVA, p<0.05) and pre- and post-treatment samples of each condition were collected. Afterwards, HPLC-coupled mass spectrometry analysis was performed (3 biological replicates with 2 technical replicates: FDR 1%). A total of 3,881 proteins were identified and label-free compared. Next, those statistically significant proteins that allowed to discriminate between conditions (Linear Discriminant Analysis p were determined and the subsequent functional enrichment analysis (Cytoscape, STRING) revealed changes in several pathways. Among them, while RS exhibited a predominance of anaerobic energy metabolism, n-RS were characterized by increased mitochondrial aerobic metabolism. In vitro treatment with 2.5M metformin (Met, mitochondrial electron chain inhibitor) significantly prevented growth n-RS (%inhibition Tz= 15.0±3.6 vs %inhibition Tz+Met= 41.1±2.7, t-test p<0.05) accentuated Tz response in RS. Interestingly, Met affected 3D architecture of n-RS. To conclude, these results highlight a key role of mitochondrial aerobic metabolism in Tz resistance and propose Met as a potential therapeutic alternative for this phenotype.
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Palabras Clave
Mammary carcinomaTrastuzumabMitochondria