The splicing machinery is dysregulated and represents a therapeutic vulnerability in breast cancer

• DOI: 10.1007/s00018-024-05515-6
• Publication Date: 2024-12-27T02:28:47Z
• Authors: Natalia Hermán-Sá...; Miguel E. G-García; Juan M. Jiménez-V...; Elena M. Yubero-S...; Laura M. López-Sá...; Sara Romero-Martín; Jose L. Raya-Pove...; Marina Álvarez-Be...; Justo P. Castaño; Raúl M. Luque; Manuel D. Gahete
• Keywords: Spliceosome; Splicing factor

Breast cancer (BCa) is a highly prevalent pathological condition (̴30% in women) with limited and subtype-dependent prognosis therapeutic options. Therefore, BCa management might benefit from the identification of novel molecular elements clinical potential. Since splicing process gaining great relevance cancer, this work analysed expression multiple Spliceosome Components (SCs = 17) Splicing Factors (SFs 26) found drastic dysregulation (n 69) vs. control (negative biopsies; n 50) samples. Among all components analysed, we highlight upregulation ESRP1 down-regulation PRPF8 NOVA1 Indeed, was specially overexpressed triple-negative (TNBCa) associated worse (i.e., higher grade lower overall survival), suggesting an association aggressiveness. On other hand, generally downregulated no associations to characteristics, while TNBCa patients aggressive tumours. Consistently, overexpression vitro reduced functional parameters aggressiveness ER-/PR- cell lines (MDA-MB-231 BT-549) but not ER+/PR+ cells (MCF7), critical role subtype-specific BCa. Finally, pharmacological inhibition machinery using pladienolide B decreased features lines, showing subtype-independent inhibitory potential, being relatively innocuous normal-like breast cells. These results demonstrate profound their potential as source promising diagnosis/prognosis markers, well valuable targets for