Molecular and Cellular Pathobiology HMGA2 Is a Driver of Tumor Metastasis

The non-histone chromatin-binding protein HMGA2 is expressed predominantly in the mesenchyme before its differentiation, but it is also expressed in tumors of epithelial origin. Ectopic expression of HMGA2 in epithelial cells induces epithelial–mesenchymal transition (EMT), which has been implicated in the acquisition of metastatic characters in tumor cells. However, little is known about in vivomodulation of HMGA2 and its effector functions in tumor metastasis. Here, we report that HMGA2 loss of function in a mouse model of cancer reduces tumor multiplicity.HMGA2-positive cellswere identifiedat the invasive frontof humanandmouse tumors. Inaddition, in a mouse allograft model, HMGA2 overexpression converted nonmetastatic 4TO7 breast cancer cells to metastatic cells that homed specifically to liver. Interestingly, expression of HMGA2 enhanced TGFb signaling by activating expression of the TGFb type II receptor, which also localized to the invasive front of tumors. Together our results argued thatHMGA2plays a critical role in EMTbyactivating theTGFb signalingpathway, thereby inducing invasion and metastasis of human epithelial cancers. Cancer Res; 73(14); 1–11. 2013 AACR.