R-spondins (roof plate-specific spondins; RSPOs) represent a group of four secreted proteins (RSPO1–4) described in vertebrates. All four RSPOs potently enhance canonical and non-canonical Wnt signaling pathways. We have recently demonstrated that Rspo3 is expressed in the basal stem cell-enriched compartment of the mouse mammary gland and that it induces epithelial-mesenchymal transition as well as mammary tumor progression. The transcription factor Runx1, which encodes a DNA-binding protein partner of the heterodimeric CBFβ complex, activates Rspo3 expression in mouse mammary tumor cells. Based on our previous studies, we propose that the expression of RSPO3, which participates in the maintenance of mammary normal and cancer stem cells, is directly regulated by RUNX-CBFβ and that blocking the activity of this complex may lead to the development of new therapeutic strategies for the treatment of breast cancer.