2. Blockade of ErbB-2 Nuclear Function Induces the Interferon Signaling Pathway in Breast Cancer Models Resistant to Trastuzumab.

CORDO RUSSO R; MADERA S; MERIN, SHARON S.; CHERVO MARÍA F; EBRAHIMIE E; SELTH L; CHIAUZZI VA; DUPONT A; BARCHUK S; FIGURELLI S; LOPEZ DELLA VECCHIA D; GUZMÁN P; ROA JC; LEVIT C; LEBERSZTEIN G; ANFUSO F; PROIETTI CJ; SCHILLACI R; HICKEY TE; TILLEY WD; ELIZALDE PV

Atlanta

Congreso; 104th Annual Meeting of the Endocrine Society.; 2022

Endocrine Society

Despite clinical efficiency of therapies targeting cell-surface receptor ErbB-2, resistance tosuch drugs is a major issue in breast cancer (BC). ErbB-2 triggers oncogenic signaling when ismembrane-bound, but it also migrates to the nucleus (NErbB-2) where it acts as atranscription regulator. Here, we explored ErbB-2 induced transcriptome using a resistantmodel of BC with high NErbB-2 levels. Eviction of NErbB-2 modulated the expression ofgenes involved in type-I interferon signaling pathway. Preclinical assays demonstrated thatblockade of NErbB-2 abrogates tumor growth and induced expression of intermediarygenes such as IFNB1, OAS2, and TRIM22. Analysis of local chromatin architecture identifiedErbB-2 constitutive recruitment onto IFNB1 regulatory regions, while its nuclear evictionresulted in high levels of histone H4 acetylation, a marker of chromatin activation. Ourfindings indicate that NErbB-2 drives the growth of TZ-resistant BC cells via transcriptionalrepression of IFNB1 signaling pathway and highlight NErbB-2 as a therapeutic target in TZ-resistant BC.