IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
ErbB-2 nuclear variants drive tumor growth and predict clinical outcome in TNBC.
Autor/es:
CHERVO MF; DE MARTINO M; PETRILLO E; IZZO F; GUZMÁN P; AMASINO MF; SCHILLACI R; PROIETTI CJ; CHARREAU EH; ELIZALDE PV; BELLORA N; CHIAUZZI VA; MADERA S; ROA JC; CORDO RUSSO RI
Lugar:
Buenos Aires
Reunión:
Congreso; LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2017
Institución organizadora:
Sociedad Argentina de Investigaciones Clinicas
Resumen:
Triple negative breast cancer (TNBC) refers to the group of tumorswith poor prognosis without clinically significant levels of estrogenand progesterone receptors, and which lack ErbB-2 overexpressionor gene amplification. Our hypothesis is that BCs defined as TN indeedexpress ErbB-2 which instead of being localized at the membraneis present in the nucleus where it modulates tumor growth. Wedetected ErbB-2 variants of different molecular weight (MW) in thenucleus of TNBC cell lines by western blot: MDA-MB-453 expressedfull-length ErbB-2 (185 kDa, p185ErbB-2); MDA-MB-468 expresseda variant of lower MW (165 kDa, p165ErbB-2); HCC-70 and MDAMB-231 expressed p185 and p165ErbB-2. Different ErbB-2 transcriptvariants were reported, among them an alternative splicedisoform lacking exon 16 (ErbB-2D16) is associated with high oncogenicand metastatic potential in BC. Here, we studied ErbB-2 transcriptvariants expression by conventional PCR using splice-specificprimers. All TNBC cells expressed high levels of the ErbB-2 variantC (NM_001289936) which is predicted to be localized in the nucleussince it lacks the N-terminal signal peptide. We also showed thatErbB-2D16 was expressed in TNBC cells. We further discover astrong NErbB-2 presence in TNBC cells by immunofluorescenceand confocal microscopy. These results were confirmed in a cohortof 57 TNBCs in which 26 patients showed NErbB-2 positivity. We revealedNErbB-2 as a significant predictor of worse overall survival inTNBC. Finally, we explored the biological relevance of NErbB-2 bytransfection with the hErbB-2DNLS mutant which is unable to translocateto the nucleus and also acts as dominant negative inhibitor ofendogenous NErbB-2 translocation. Blockade of NErbB-2 presenceinhibited TNBC cell proliferation and tumor growth in TNBC xenografts.In conclusion, our results identified NErbB-2 variants as keyplayers in TNBC and highlighted NErbB-2 as potential biomarkerand therapeutic target in these tumors.