Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumours
Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le proto-oncogène Bcl3 dans le processus métastatique d'un cancer du sein ErbB2+
Bcl3 is a putative proto-oncogene deregulated in hematopoietic and solid tumours. 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 tumours 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 tumours without affecting primary tumour growth or normal mammary function. Deletion of the Bcl3 gene in ErbB2 positive (MMTV-Neu) mice resulted in a 75% reduction in metastatic tumour 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 tumour growth, cyclinD1 levels or caspase 3 activity. Direct inhibition of Bcl3 by siRNA in a transplantation model of an Erbb2-positive mammary tumour cell line confirmed the effect of Bcl3 in malignancy suggesting that the effect of Bcl3 was intrinsic to the tumour cells. Bcl3 knockdown resulted in a 61% decrease in tumour cell motility and a concomitant increase in the cell migration inhibitors Nme1, Nme2, 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 tumour growth.