[Show abstract][Hide abstract] ABSTRACT: Overexpression of the ErbB2 receptor tyrosine kinase in breast cancer contributes to tumor development and is associated with poor prognosis. However, the mechanism by which ErbB2 might contribute to metastasis is not well defined. To identify genes that mediate ErbB2-driven cell motility, we performed differential gene expression analysis of ErbB2-expressing migrating breast cancer cells vs mutant ErbB2-expressing non-migrating cells. Among the genes that were specifically induced in migrating cells were known transcriptional targets of ErbB2, such as matrix metalloproteinases, and novel ErbB2 targets. Contribution of selected candidate genes to ErbB2-driven cell motility was tested by small interfering RNA targeting. Knockdown of the soluble form of ST2 (sST2), also called interleukin-1 receptor-like 1, one of the most robustly induced genes, decreased ErbB2-induced cell motility in two different cell lines. In response to ErbB2 activation, sST2 protein expression and secretion were increased. Moreover, recombinant sST2 associated with the plasma membrane and sST2-blocking antibodies reduced ErbB2-induced motility. Interestingly, cells from metastatic breast tumors secreted higher levels of sST2 than primary tumor cells. Finally, sST2 was found at high levels in the serum of metastatic breast cancer patients. Our data suggest that sST2 contributes to breast cancer cell motility and that sST2 secretion is associated with metastasis.