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Background: Metastasis is most often the root cause of cancer-related death. Human short stature homeobox 2 (SHOX2), a homeodomain transcription factor, is a novel inducer of epithelial-to-mesenchymal transition in breast cancer cells, though its exact role and underlying mechanisms in metastasis are not well understood. Methods: TCGA analysis was performed to identify the clinical relevance of SHOX2 in breast cancer. Gene depletion was achieved by short hairpin RNA and small interfering RNA. Molecular regulations and alterations were assessed by Western blotting, immunoprecipitation, immunohistochemistry, qRT-PCR, chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR), and ChIP/re-ChIP. The impact of SHOX2 signaling on tumor growth and metastasis was evaluated in orthotopic breast tumor mice. Results: The expression level of SHOX2 is strongly associated with poor distant metastasis-free survival in breast cancer patients and inactivation of SHOX2 suppresses breast tumor growth and metastasis in mice. In breast cancer cells, SHOX2 directly activates Wiskott-Aldridge syndrome protein family member 3 (WASF3), a metastasis-promoting gene, at the transcriptional level, leading to a significant increase in metastatic potential. Mechanistically, SHOX2 activates signal transducer and activator of transcription 3 (STAT3) and recruits it to the WASF3 promoter, where STAT3 cooperates with SHOX2 to form a functional immunocomplex to promote WASF3 transcriptional activity in breast cancer cells. WASF3 knockdown abrogates SHOX2-induced metastasis, but not SHOX2-dependent tumorigenesis. Conclusions: These findings provide a critical link between the SHOX2-STAT3-WASF3 signaling axis and metastasis and suggest that the targeting of this signaling node may represent a valuable alternative strategy for combating breast cancer metastasis. [ABSTRACT FROM AUTHOR]