This latter function appears to be key to the oncogenic role of Wnt signaling. In gut, the mutation of key tumor suppressor molecules in the Wnt signaling pathway leads to amplification of stem/progenitor compartments, followed by the appearance of differentiated adenomas and tumors. Our previous data has shown that gain of function of Wnt signaling in mammary Gentamycin Sulfate glands also induces an increase in the stem/progenitor cell activity in the preneoplastic condition. In order to understand the normal function of Wnt signaling in mammary glands, we chose to study how loss of function of Wnt signaling affected mammary development. There are many Wnt-dependent signaling events, but only one pathway has so far been associated with the stem cell functions and oncogenic properties. This so-called canonical pathway is mediated by the interaction of Wnt ligands with a pair of cell surface receptors, comprising a Frizzled receptor and an Lrp5 or 6 receptor. Binding of the Wnt ligand to the Frizzled and Lrp5/6 receptor is followed by the recruitment of axin from the bcatenin destruction complex, stabilization of b-catenin and, transactivation of specific target genes via a b-catenin/TCF complex. There are many members of the Wnt family of secreted lipoglycoprotein ligands, and several are expressed during mammary gland development. Similarly, there are 10 known Frizzled homologues, of which Frizzled 1�C8 are known to be expressed in mammary epithelial cells. However, there is an absolute requirement for either Lrp5 or Lrp6 for canonical Wnt signaling. Lrp5 and -6 belong to the LDL receptor related protein family of single-span transmembrane receptors, which mediate binding and internalization of various lipoprotein particles. Current studies have not addressed whether Lrp5 and Lrp6 have distinct molecular properties. Ablation of Lrp5 and Lrp6 produce entirely different phenotypes in mice. Lrp6 expression appears to be widespread in embryonic tissues and is essential for embryonic development. Mammary development fails in the absence of Lrp6; both epithelial outgrowth of the placode and the formation of the host adipose tissue is affected. The role of Lrp6 in adult tissues is unclear, but loss of function mutations have been linked with human cases of Atropine sulfate coronary artery disease. In contrast, Lrp5 null mice are viable, although they exhibit defects in bone ossification and vascularization of the eye. In adult tissues, Lrp5 mRNA and protein levels are high and widely expressed in tissues such as bone, pancreas, central nervous system, and in phagocytic cells. Loss of function mutations have been associated with heritable cases of osteoporosis as well as Type I diabetes. In the mammary gland, Wnt signaling is required for specification and outgrowth of the mammary rudiment from the embryonic skin, and a Wnt reporter strain shows high Wnt signaling activity at this stage. Since inhibition of Wnt signaling prevents gland formation, it has been difficult to determine the functional role of Wnt signaling in later and adult stages of mammary gland development. Wnt signaling has been shown to be important not only to the maintenance of stem/progenitor compartments in gut, but in a number of other cell lineages. These include hematopoetic and embryonic stem cells. Specifically, several components of the canonical Wnt signaling pathway have been found to be expressed in both embryonic and hematopoetic stem cell populations. Moreover, treatment with Wnt ligands or downstream activation of the Wnt signaling pathway inhibits differentiation and promotes self-renewal of these cells.