ARTICLE ABSTRACTEpithelial–mesenchymal transition (EMT) is a developmental program, which is associated with breast cancer progression and metastasis. Here, we report that ectopic overexpression of SOX4 in immortalized human mammary epithelial cells is sufficient for acquisition of mesenchymal traits, enhanced cell migration, and invasion, along with epithelial stem cell properties defined by the presence of a CD44high/CD24low cell subpopulation. SOX4 positively regulated expression of known EMT inducers, also activating the TGF-β pathway to contribute to EMT. SOX4 itself was induced by TGF-β in mammary epithelial cells and was required for TGF-β–induced EMT. Murine xenograft experiments showed that SOX4 cooperated with oncogenic Ras to promote tumorigenesis in vivo. Finally, in clinical specimens of human breast cancer, we found that SOX4 was abnormally overexpressed and correlated with the triple-negative breast cancer subtype (ER−/PR−/HER2−). Our findings define an important function for SOX4 in the progression of breast cancer by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease. Cancer Res; 72(17); 4597–608. ©2012 AACR.