We observed that the basal level expression of the interferon inducible gene, N-Myc interactor (Nmi), was low in aggressive breast cancer cell lines. However its expression in the aggressive lines was inducible by interferon-\#947; (IFN-\#947;). To specifically test the downstream effects of IFN-\#947; stimulated expression of Nmi, we established stable expressors of Nmi in MDA-MB-231 and MDA-MB-435 cell lines. Functional studies using these Nmi-expressing cells showed that constitutive expression of Nmi reduced the ability of the tumor cells for invasion, anchorage independent growth. It also reduced their tumor growth in vivo as tested in nude mouse studies. Our investigations further revealed that the expression of Dkk1, a secreted inhibitor of Wnt/\#946;-catenin signaling, was significantly upregulated in the Nmi expressing clones concurrent with reduced levels of \#946;-catenin, the critical transcription co-factor of Wnt pathway. Treatment of the Nmi expressors with blocking antibody to Dkk1 restored \#946;-catenin protein levels. Dkk1 halts Wnt-signaling by targeting \#946;-catenin for proteasome-mediated degradation. c-Myc is a known downstream target of activated \#946;-catenin signaling. Treatment of Nmi expressors with the proteosome inhibitor MG132, resulted in elevated \#946;-catenin levels with concomitant elevation of c-Myc protein levels. In summary, our data suggests that overexpression of Nmi inhibits the Wnt/\#946;-catenin signaling via upregulation of Dkk1 and retards tumor growth.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4949.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO