Specifically Inhibits Tumorigenesis Cyclooxygenase-2 and Osteopontin under Conditions in Dominant-Negative Activator Protein 1 (TAM67) Targets

Activation of activator protein 1 (AP-1) and nuclear factor KB (NFKB)–dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFKB activation by interacting with NFKB p65. Two-stage [7,12dimethylbenz(a)anthracene (DMBA)/12-O -tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67–expressing mice results in dramatic inhibition of tumor promoter–induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPAor E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1– and/or NFKB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA–induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFKB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter. [Cancer Res 2007;67(6):2430–8]