Molecular and Cellular Pathobiology Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumors. Studies in cell lines suggest that its oncogenic effects are mediated through the induction of proliferation and inhibition of cell death, yet its role in endogenous solid tumors has not been established. Here, we address the oncogenic effect of Bcl3 in vivo and describe how this Stat3-responsive oncogene promotes metastasis of ErbB2-positive mammary tumors without affecting primary tumor growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2-positive (MMTV-Neu)mice resulted in a 75% reduction inmetastatic tumor burden in the lungswith a 3.6-fold decrease in cell turnover index in these secondary lesions with no significant effect on primary mammary tumor growth, cyclin D1 levels, or caspase-3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2positivemammary tumor cell line confirmed the effect of Bcl3 inmalignancy, suggesting that the effect of Bcl3was intrinsic to the tumor cells. Bcl3 knockdown resulted in a 61% decrease in tumor cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, and Nme3, the GDP dissociation inhibitor Arhgdib, and the metalloprotease inhibitors Timp1 and Timp2. Independent knockdown of Nme1, Nme2, and Arhgdib partially rescued theBcl3motility phenotype. These results indicate for thefirst time a cell-autonomous disease-modifying role for Bcl3 in vivo, affectingmetastatic disease progression rather than primary tumor growth. Cancer Res; 73(2);