HER2-driven breast cancer suppression by the JNK signaling pathway.

Abstract

The HER2⁺ subtype of human breast cancer is associated with the malignant transformation of luminal ductal cells of the mammary epithelium. The sequence analysis of tumor DNA identifies loss of function mutations and deletions of the <i>MAP2</i><i>K4</i> and <i>MAP2</i><i>K7</i> genes that encode direct activators of the JUN NH₂-terminal kinase (JNK). We report that in vitro studies of human mammary epithelial cells with CRISPR-induced mutations in the MAPK and MAP2K components of the JNK pathway caused no change in growth in 2D culture, but these mutations promoted epithelial cell proliferation in 3D culture. Analysis of gene expression signatures in 3D culture demonstrated similar changes caused by HER2 activation and JNK pathway loss. The mechanism of signal transduction cross-talk may be mediated, in part, by JNK-suppressed expression of integrin α6β4 that binds HER2 and amplifies HER2 signaling. These data suggest that HER2 activation and JNK pathway loss may synergize to promote breast cancer. To test this hypothesis, we performed in vivo studies using a mouse model of HER2⁺ breast cancer with <i>Cre/loxP</i>-mediated ablation of genes encoding JNK (<i>Mapk8</i> and <i>Mapk9</i>) and the MAP2K (<i>Map2</i><i>k4</i> and <i>Map2</i><i>k7</i>) that activate JNK in mammary epithelial cells. Kaplan-Meier analysis of tumor development demonstrated that JNK pathway deficiency promotes HER2⁺-driven breast cancer. Collectively, these data identify JNK pathway genes as potential suppressors for HER2⁺ breast cancer.