Cancer esearch cular and Cellular Pathobiology ical Roles of DMP 1 in Human Epidermal Growth Factor eptor 2 / neu-Arf-p 53 Signaling and Breast R cer Development
Download an epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated hile it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is wn. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3′-kinaseF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpresoth Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu and mammary tumorigenesis was significantly accelerated in both Dmp1 and Dmp1 mice. Seleceletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu omas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1, Dmp1, and pe neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21, ng p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, enous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study endog shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis. Cancer Res; 70(22); 9084–94. ©2010 AACR.