siRNAs targeting alternative transcript variants of ErbB-2 as novel therapy in triple negative breast cancer

PETRILLO E; CENCIARINI, M; PROIETTI, CJ; ROSALIA CORDO RUSSO; PETRILLO E; CENCIARINI, M; PROIETTI, CJ; ROSALIA CORDO RUSSO; CHERVO, MF; DE MARTINO M; CHIAUZZI V; SCHILLACI, R; CHERVO, MF; IZZO F; DE MARTINO M; MADERA S; CHIAUZZI V; CHARREAU, EH; SCHILLACI, R; ELIZALDE, PATRICIA V.; IZZO F; MADERA S; CHARREAU, EH; ELIZALDE, PATRICIA V.

Congreso; RNA Therapeutics: From Mechanism to Therapy; 2019

Triple negative breast cancer (TNBC) refers to the group of tumors (15-20%) with poor prognosis, which do not express estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2, a receptor tyrosine kinase. Tumor heterogeneity and the presence of several TNBC subtypes may explain why there are neither clinical biomarkers nor targeted therapies for this disease. Notably, in human cell lines from all TNBC subtypes we detected nuclear expression of wild-type ErbB-2 (185kDa) and of an ErbB-2 isoform of lower molecular weight (MW) (165kDa, p165ErbB-2). Our findings on ErbB-2 alternative splicing using a PCR-sequencing approach revealed the expression of ErbB-2 transcript 3 (T3, NM_001289936) encoding the isoform ?c? (NP_001276865) in TNBC cells. To explore whether p165ErbB-2 corresponds to the isoform c, we designed a set of siRNAs targeting T3 (T3siRNAs). Strikingly, transfection of TN cells and tumors with T3siRNAs silenced p165ErbB-2 expression, demonstrating that isoform c has a MW of 165kDa on SDS-PAGE. Most importantly, T3siRNAs inhibited TN cell proliferation and tumor growth. We propose T3siRNAs as a novel targeted therapy for TNBC.