Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth

CHERVO, MARIA F; CORDO RUSSO, ROSALÍA I.; PETRILLO E; IZZO, F.; DE MARTINO, M; BELLORA N; CENCIARINI M; CHIAUZZI VA; SANTA MARIA DE LA PARRA L; PEREYRA MG; GUTTLEIN L; PODHAJCER O; DANIOTTI JL; DUPONT A; BARCHUK S; FIGURELLI S; LOPEZ DELLA VECCHIA D; ROA JC; GUZMÁN P; PROIETTI CJ; SCHILLACI R; ELIZALDE PV

Oncogene

Springer Nature

Año: 2020 vol. 39 p. 6245 - 6262

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen andprogesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosinekinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinicalbiomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for earlyand metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2).Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interferencestrategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or thenon-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in thenucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumorgrowth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but alsoisoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoverieschallenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins,which conserve the canonical domains and are located in their classical cellular compartments.