Chromatin Modifications Sequentially Enhance ErbB2 Expression in ErbB2-Positive Breast Cancers

ErbB2 gene amplification occurs in 20%–25% of breast cancers, and its therapeutic targeting has markedly improved survival of patients with breast cancer in the adjuvant setting. However, resistance to these therapies can develop. Because epigenetic mechanisms can importantly influence oncogene expression and be druggable as well, we investigated histone modifications that influence ErbB2 overexpression, independent of gene amplification. We demonstrate here that ErbB2-overexpressing breast carcinomas acquire the H3K4me3 mark on the erbB2 promoter and that receptor-amplified tumors further acquire the H3K9ac mark, which is dependent on H3K4me3 mark acquisition. Targeting WD repeat domain 5 (Wdr5), which is absolutely required for H3K4me3 enrichment, decreased ErbB2 overexpression, associated with a decrease in the H3K4me3 mark on the erbB2 promoter. Of note, Wdr5 silencing cooperated with trastuzumab or chemotherapy in specifically inhibiting the growth of ErbB2-positive breast tumor cells. Thus, our studies illuminate epigenetic steps in the selection for ErbB2 activation. [Display omitted] •ErbB2 promoters are enriched with H3K4me3, alone or with H3K9ac mark•Targeting H3K4me3 reduces ErbB2 in all ErbB2-positive lines•Targeting H3K9ac reduces ErbB2 specifically in ErbB2-amplified lines.•Wdr5 silencing cooperates with trastuzumab or cisplatin therapy Current therapy for ErbB2/HER2-positive breast cancers targets this receptor, although resistance can develop. In this study, Aaronson and colleagues show that ErbB2-overexpressing breast carcinomas acquire the H3K4me3 mark, mediated by an MLL complex, on the erbB2 promoter. Receptor-amplified tumors further acquire the H3K9ac mark in a stepwise manner, increasing expression per gene copy. The authors show that targeting Wdr5, a component of an MLL complex, cooperates with trastuzumab or chemotherapy to specifically inhibit the growth of erbB2-positive breast tumor cells.