Proteomic Characterization of a 3D HER2+ Breast Cancer Model Reveals the Role of Mitochondrial Complex I in Acquired Resistance to Trastuzumab.
Ivana J TapiaDavide PericoVirginia J WolosMarcela Solange VillaverdeMarianela AbrigoDario Di SilvestrePietro Luigi MauriAntonella De PalmaGabriel L FiszmanPublished in: International journal of molecular sciences (2024)
HER2-targeted therapies, such as Trastuzumab (Tz), have significantly improved the clinical outcomes for patients with HER2+ breast cancer (BC). However, treatment resistance remains a major obstacle. To elucidate functional and metabolic changes associated with acquired resistance, we characterized protein profiles of BC Tz-responder spheroids (RSs) and non-responder spheroids (nRSs) by a proteomic approach. Three-dimensional cultures were generated from the HER2+ human mammary adenocarcinoma cell line BT-474 and a derived resistant cell line. Before and after a 15-day Tz treatment, samples of each condition were collected and analyzed by liquid chromatography-mass spectrometry. The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients. In conclusion, the non-responder phenotype identified here provides a signature of proteins and related pathways that could lead to therapeutic biomarker investigation.
Keyphrases
- mass spectrometry
- liquid chromatography
- end stage renal disease
- endothelial cells
- epidermal growth factor receptor
- squamous cell carcinoma
- ejection fraction
- chronic kidney disease
- cell proliferation
- young adults
- combination therapy
- high resolution mass spectrometry
- cell death
- transcription factor
- smoking cessation
- peritoneal dialysis
- reactive oxygen species
- replacement therapy
- drug induced
- locally advanced
- tyrosine kinase
- data analysis