CREB1-BCL2 drives mitochondrial resilience in RAS GAP-dependent breast cancer chemoresistance

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Triple-negative breast cancer (TNBC) is an aggressive and heterogenous subtype. RASAL2 a RAS GTPase-activating protein (GAP) that has been associated with platinum resistance in TNBC, but the underlying mechanism unknown. Here, we show enriched following neoadjuvant chemotherapy TNBC patients. This enrichment specific to tumour compartment compared adjacent normal tissues, suggesting upregulation tumour-selective. Analyses based on 2D/3D cultures patient-derived xenograft models reveal confers cross-resistance common DNA-damaging chemotherapies other than platinum. Mechanistically, found apoptotic signalling significantly downregulated upon expression. feature characterised by substantial alterations expression of anti-versus pro-apoptotic factors, pointing heterogeneous mechanisms. In particular, upregulates BCL2 via activation oncogenic transcription co-factor YAP. CREB1, YAP-interacting protein, was identified as factor binds promoter regions BCL2, driving their collective A subset colocalises subcellularly. Both proteins decorate mitochondria, where high levels mitochondrial RASAL2-induced render organelles refractory apoptosis. Accordingly, outer membrane permeabilisation assay using live mitochondria from RASAL2-high/chemoresistant cells demonstrated attenuated release death signal, cytochrome c, when exposed factors BAX tBID. Similarly, these were more resilient towards chemotherapy-induced depolarisation. Together, this work reveals previously undocumented molecular link between GAP apoptosis regulation, providing new mechanistic framework for targeting chemorefractory tumours.

Language: Английский

The role and function validation of P2RX4 as a novel cancer biomarker in pan-cancer analysis

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 3, 2025

Language: Английский