These parallels suggests that although the regulation of progenitor cells by ovarian steroids may differ in higher mammals, the localized growth factor signaling pathways that are ultimately responsible for their proliferation may be conserved between species. WNT signaling has been shown to be important for stem cell regulation multiple epithelial tissues and in many organisms. The WNT family is complex, made up of multiple receptors Histamine Phosphate including Frizzled, LRP5, and LRP6, as well as secreted ligands and inhibitors with limited GSK J1 ability to diffuse in the mammary matrix. Our data demonstrate that WNT signaling through LRP6 regulates both acinar and ductal colony formation. The specificity of WNT signaling to each progenitor type may be regulated by cell type specific expression of receptors including basal cell expression of LRP5, as well as secretion of inhibitors, DKK and SFRP. In the murine mammary gland, DKK3 expression is enriched in the basal epithelium suggesting that this may be a point of regulation. We have also demonstrated that TBX3 upregulates WNT9A expression, a novel WNT protein not previously characterized for its role in the mammary gland or stem cell activity. Thus, the regulation and specificity of specific WNT ligands is likely to be important in WNT activity. Interestingly, mutations in TBX3 have recently been identified in breast cancers suggesting that misregulation of TBX3 may be important for the genesis and pathobiology of breast cancer. Indeed, estrogen has recently been reported to expand breast cancer stem-like cell cells through upregulation of TBX3. Furthermore, TBX3 activity is increased by WNT signaling in various cancer cell lines. These observations, suggest that estrogen signaling and TBX3 mutations in the context of breast cancer may be important for deregulating stem/progenitor cell activity, a prerequisite for neoplastic transformation. Further studies will be necessary to characterize the role and biological significance of TBX3 mutations in breast tumors and how they synergize with estrogen to drive cancer.