Nuclear ErbB-2 activity modulates the interferon signalling pathway in breast cancer cells resistant to anti-ErbB-2 therapies.

CORDO RUSSO RI; MADERA S; CHERVO MF; EBRAHIMIE E; SELTH L; CHIAUZZI VA; KIKHTYAK Z; PROIETTI CJ; SCHILLACI R; CHARREAU EH; HICKEY TE; TILLEY WD; ELIZALDE PV

Adelaide

Congreso; 7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting; 2019

PacRim Breast and Prostate Cancer Group

Overexpression of ErbB-2, a member of ErbB family of receptor tyrosine kinases, occursin 15?20% of breast cancers (BC) and is considered a major oncogenic driver. Despiteclinical efficiency of ErbB-2-targeted therapies (e.g. trastuzumab), resistance to saiddrugs is a major issue. While ErbB-2 is mainly a cell membrane-bound receptor, it canmigrate to the nucleus (NErbB-2) where it acts as a transcription factor or coactivator. Werevealed that NErbB-2 is a major proliferation driver in trastuzumab-resistant BC. Here,we used JIMT-1 BC cells, which constitutively express NErbB-2 and are intrinsicallytrastuzumab-resistant, to explore the transcriptional consequences of NErbB-2 activity.RNAseq was performed on JIMT-1 cells transfected with and without a human ErbB-2nuclear localization domain mutant (hErbB-2ΔNLS), unable to translocate to the nucleus,which acts as a dominant negative inhibitor of endogenous NErbB-2 migration. Exclusionof ErbB-2 from the nucleus resulted in up-regulation of 280 genes and down-regulation of33 genes. Functional analysis using String Database revealed that blockade of NErbB-2presence increased expression of genes involved in type-I interferon and cytokinemediatedsignaling pathways (FDR 7.52E-34 and 4.48E-32, respectively). Interferon beta(IFNβ) and lambda (IFNλ), key players in interferon signaling, were among top upregulatedgenes. In independent validation experiments, blockade of NErbB-2 inducedIFNβ and IFNλ mRNA expression in JIMT-1 and HCC-1569 trastuzumab-resistant cells.hErbB-2ΔNLS also induced TRIM22 and OAS-2 mRNA expression, two proteinsactivated by interferon signaling. JIMT-1 xenografts demonstrated that blockade ofNErbB-2 localization by injection of hErbB-2ΔNLS significantly inhibits in vivo tumorgrowth. Interestingly, IFNβ and IFNλ mRNA levels were also up-regulated in hErbB-2ΔNLS-injected tumors. Moreover, treatment with IFNβ or IFNλ inhibited in vitroproliferation of JIMT-1 cells. Collectively, these findings reveal IFNβ and IFNλ as noveltargets of NErbB-2 and suggest that NErbB-2 drives the growth of trastuzumab-resistantBC cells via transcriptional repression of interferons.