Targeting ErbB-2 nuclear function induces the interferon signalling pathway in breast cancer.

MADERA S; CORDO RUSSO R; CHERVO MF; EBRAHIMIE E; SELTH L; CHIAUZZI VA; DUPONT A; PROIETTI, CECILIA J.; SCHILLACI R; HICKEY TE; TILLEY WD; ELIZALDE PV

Simposio; Buenos Aires Breast Cancer Symposium BA-BCS2020; 2021

ErbB2, a member of ErbB family of receptor tyrosine kinases, is an oncogenic driver in breast cancer (BC). Despite clinical efficiency of ErbB2-targeted therapies (trastuzumab, TZ), resistance to drugs is a major issue. ErbB2 is a membrane-bound receptor, but also migrates to the nucleus (NErbB2) to act as a transcription factor/coactivator. We reported the paramount importance of NErbB2 in TZ-resistant BC; now, we used a TZ-resistant model with high basal NErbB2 levels to explore its induced transcriptome. RNAseq was run on JIMT1 cells transfected or not with an ErbB2 nuclear localization domain mutant, which is also a dominant-negative inhibitor of endogenous NErbB2 migration. Exclusion of NErbB2 modulated the expression of nearly 300 genes. Functional analysis revealed that NErbB2 blockade enriched the expression of genes involved in type-I interferon signaling pathway. IFNB1, OAS2 and TRIM22 were among the top modulated genes. In independent validation experiments, blockade of NErbB2 induced expression of these genes in different models of BC. In vivo experiments demonstrated that blockade of NErbB2 significantly inhibits tumor growth and induced mRNA expression of these genes. ChIP assays revealed recruitment of ErbB2 onto IFNB1 coding and promoter regions in normal growth conditions. These results reveal the repression of the type-I interferon pathway as a mechanism of carcinogenesis in ErbB2-positive BC and essentially highlight NErbB2 as a therapeutic target in TZ-resistant BC.