Science and Technology Production
Congress
Authorship
Tapia, Ivana
;
Perico, Davide
;
De Palma, Antonella
;
Wolos, Virginia J
;
VILLAVERDE, MARCELA SOLANGE
;
Mauri, Pier L
;
Rocca,
;
Abrigo, M
;
Silvestre,
;
Fiszman G.L
Date
2022
Publishing House and Editing Place
scielo
Summary
Information provided by the agent in
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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Key Words
Mammary carcinomaTrastuzumabMitochondria