Experiments in a mouse model of breast cancer metastasis to the lung showed that deficiency of either Myc, Skp2 or Miz1 restricted metastasis, while overexpression of each of the three proteins increased cell migration and invasion. Skp2 knockdown, for example, resulted in no metastatic nodules in the lung, compared with an average of 40 nodules when Skp2 was expressed.

Directly knocking down RhoA expression produced the same effect as blocking the Myc-Skp2-Miz1 complex. Knocking down expression of p300 resulted in decreased expression of RhoA.

In the analysis of prostate cancer tumors, expression of RhoA, Myc, Skp2 and Miz1 were significantly correlated with metastasis. Expression of the RhoA and the Myc-Skp2-Miz1 complex also were highly correlated.

Lin and colleagues note that Miz1 is thought to be a tumor-suppressor that contends with the oncogene Myc to regulate genes. In this case, the tumor-suppressor cooperates with the oncogene to launch RhoA and promote metastasis.

"Right now, there are no small-molecule agents to inhibit any of these targets," Lin said. "One future direction of research will be to find ways to target the entire transcription complex or its individual components."

Source: University of Texas M. D. Anderson Cancer Center