Critical roles of DMP1 in HER2/neu-Arf-p53 signaling and breast cancer development

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-11, Vol.70 (22), p.9084-9094
• Main Authors: Taneja, Pankaj, Maglic, Dejan, Kai, Fumitake, Sugiyama, Takayuki, Kendig, Robert D., Frazier, Donna P., Willingham, Mark C., Inoue, Kazushi
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-0159

HER2 overexpression stimulates cell growth in p53 -mutated cells while it inhibits cell proliferation in those with wild-type p53 , but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the PI3K-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was demonstrated to the Dmp1 promoter and that of Dmp1 to the Arf promoter upon HER2/neu overexpression. Both Dmp1 and p53 were induced in pre-malignant lesions from MMTV- neu mice and mammary tumorigenesis was significantly accelerated in both Dmp1 +/− and Dmp1 −/− mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50 % of wild-type HER2/neu carcinomas while the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1 +/− , Dmp1 −/− , and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21 Cip1/WAF1 , showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous h DMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study demonstrates the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.