Promotion of breast cancer by the DNPH1 enzyme.

To broaden understanding of breast cancer pathophysiology, we investigated the highly understudied DNPH1 enzyme in this disease. We found that DNPH1 is overexpressed in breast and also in prostate and lung tumors, correlating with disease aggressiveness. DNPH1 downregulation diminished the oncogenic potential of breast cancer cells and compromised respective stem cells. Likewise, DNPH1 ablation decreased the oncogenicity of lung cancer cells. Knockout of Dnph1 in mice revealed that DNPH1 is not essential for development, yet crucial for HER2-mediated mammary tumor formation. Notably, Dnph1 knockout reduced angiogenesis in HER2-induced mammary tumors and elevated AMP levels. This was accompanied by increased AMP-activated protein kinase activity and phosphorylation of YAP1, implying tapered activity of the YAP1 oncoprotein. These data have extensively shed light onto the cellular and physiological functions of the enigmatic DNPH1 protein in cancer. Overall, this highlights that DNPH1 is a promising target for cancer therapy.