Critical roles of DMP1 in human epidermal growth factor receptor 2/neu-Arf-p53 signaling and breast cancer development.
Taneja P, Maglic D, Kai F, Sugiyama T, Kendig RD, Frazier DP, Willingham MC, Inoue K
Departments of Pathology and Cancer Biology and Graduate Program in Molecular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, North Carolina.
Human epidermal growth factor receptor 2 (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 phosphatidylinositol-3′-kinase-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 [?] promoter and that of Dmp1 [?] to the Arf promoter on HER2/neu overexpression. Both Dmp1 [?] and p53 were induced in premalignant lesions from mouse mammary tumor virus-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, although 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 p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 [?] deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 [?] in HER2/neu-p53 signaling and breast carcinogenesis.
Cancer Res. (2010)
PMID: 21062982 Fulltext – Related articles – Download citation