From the pregnancy-dependent mouse mammary tumor TPDMT-4, four autonomous sublines were established after its independent progression under different conditions. Despite their similar growth rates in inguinal fat pads, three sublines formed lung metastases, and one did not when they were injected i.v. into mice as a single cell suspension. The TPDMT-4 tumor and the nonmetastatic subline expressed mRNA for the orf gene of mouse mammary tumor virus, whereas all metastatic sublines did not. This suggested that the loss of its expression may have been a prerequisite for the progression toward metastatic ability. To identify the gene(s) participating in the generation and the progression of TPDMT-4, the expression of 23 different oncogenes was analyzed. The expression of int-2 was detected in TPDMT-4 and in all sublines, indicating that TPDMT-4 was generated by activation of this gene, whereas hst expression occurred only in the metastatic sublines. These results demonstrated that the hst gene may contribute to tumor progression from a nonmetastatic to a metastatic phenotype in the mouse mammary tumor system.