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.