Nuclear Localization of ErbB-2 in Breast Cancer Regulates Interferon Pathway and Gene Expression

MADERA S; CORDO RUSSO R; CHERVO MARÍA F; EBRAHIMIE E; SELTH L; CHIAUZZI VA; DUPONT A; PROIETTI CJ; SCHILLACI R; HICKEY TE; TILLEY WD; ELIZALDE P V

Simposio; Cancer Cell Symposium: Overcaming Therapy Resistance in Cancer; 2021

Despite clinical efficiency of therapies targeting cell-surface receptor ErbB-2, resistance to such drugs is a major issue in breast cancer (BC). ErbB-2 triggers oncogenic signaling when is membrane-bound, but it also migrates to the nucleus (NErbB-2) where it acts as a transcription regulator. Here, we explored ErbB-2 induced transcriptome using a resistant model of BC with high NErbB-2 levels. Eviction of NErbB-2 modulated the expression of genes involved in type-I interferon signaling pathway. Preclinical assays demonstrated that blockade of NErbB-2 abrogates tumor growth and induced expression of intermediary genes such as IFNB1, OAS2, and TRIM22. Analysis of local chromatin architecture identified ErbB-2 constitutive recruitment onto IFNB1 regulatory regions, while its nuclear eviction resulted in high levels of histone H4 acetylation, a marker of chromatin activation. These results revealed repression of type-I interferon pathway as a mechanism of carcinogenesis in ErbB-2-positive BC highlighting NErbB-2 as a therapeutic target in resistant BC.