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Homeobox (Hox) genes encode transcription factors that act as critical regulators of growth and differentiation during embryogenesis. While many studies have identified increased expression of Hox genes in tumors, much less is known about the mechanistic basis by which Hox genes facilitate tumor development. In this issue of the JCI, McCoy and colleagues show that transgenic mice that express the homeoprotein Six1 in mammary epithelial cells show increases in stem/progenitor cell populations and subsequent tumor development, while in a separate study Micalizzi and colleagues show that overexpression of Six1 facilitates breast cancer cell metastasis by inducing epithelial-mesenchymal transition (EMT) (see the related articles beginning on pages 2663 and 2678, respectively). Their findings implicate Six1 as a central mediator of breast cancer development.