Metastatic relapse of breast cancer and other tumor types usually occurs several years after surgical resection of the primary tumor. Early dissemination of tumor cells followed by an extended period of dormancy is thought to explain this prevalent clinical behavior. We are using a gain-of-function retroviral cDNA screen in the mouse to identify genes that induce solitary mammary carcinoma cells to exit from dormancy at lung metastatic sites. In this system, retroviral cDNA libraries from highly metastatic cancer cells are transduced into target cells that undergo dormancy upon extravasation in the lung stroma. The transduced cells are then injected in the mammary fat pad of mice. After a lag time, the mice are sacrificed and cancer cells that have acquired full metastatic ability and colonized the lung are isolated from individual lesions. Finally, rescue and sequencing of the integrated provirus allows identification of the cDNA and confirmation of its pro-metastatic capacity. By using this approach, Hua Gao has discovered a discrete set of genes that enable extravasated tumor cells to exit from dormancy at lung metastatic sites. Using a similar approach, Ai Ping Lee-Lim has identified a set of microRNAs that produce the same effect. We are studying the mechanisms by which these genes and microRNAs promote reactivation at lung metastatic sites. Furthermore, we are extending this approach to study the entry into and exit from dormancy at other metastatic sites.