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 in metastatic
tumor burden in the lungs with 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 Erbb2-positive mammary tumor cell line confirmed the effect of Bcl3 in
malignancy, suggesting that the effect of Bcl3 was 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 the Bcl3 motility phenotype. These results indicate for the first time a cell-autonomous disease-modifying role for Bcl3 in vivo, affecting metastatic
disease progression rather than primary
tumor growth.