Gankyrin promotes breast cancer cell metastasis by regulating Rac1 activity.

Tumor metastasis is responsible for most cancer patients' deaths. Understanding the mechanism of metastasis is crucial for improving the cure rate for cancer. Here, we report that Gankyrin, a chaperone of ubiquitin-proteasome, has an essential role in breast cancer metastasis. We find that Gankyrin is highly overexpressed in human breast cancers and the expression correlates strongly with lymph node metastasis. Knocking down Gankyrin expression in highly metastatic human breast cancer cells significantly decreases cancer cell migration and invasion. Furthermore, we demonstrate that depletion of Gankyrin inhibits intrinsic Rac1 activity and induces large focal adhesions. Overexpression of Gankyrin accelerates focal adhesion turnover and increases cell migration. Notably, reduction of Gankyrin expression in mouse mammary tumor cell significantly decreases tumor metastasis to lung in animal models. Therefore, our findings suggest that Gankyrin is crucial for breast cancer metastasis and highlight the potential of Gankyrin as a therapeutic target for tumor metastasis.