In addi tion, aberrantly activated Wnt signaling leads to inappropriate mammary gland development and mam mary tumorigenesis in mice. The Wnt family of secreted proteins is implicated in the regulation of cell fate during development, as well as in cell proliferation, TW-37 clinical trial morphology, and migration. The best characterized Wnt pathway is the canonical Wnt catenin pathway whereby Wnt signaling leads to the stabi lization of catenin and activation of catenin respon sive gene expression. Wnt ligands activate the Wnt catenin signaling pathway by binding to receptors com prised of Frizzled proteins in conjunction with one of the LDL receptor related proteins LRP5 or LRP6. Receptor activation results in the ability of a cytoplasmic protein, Dishevelled, to inhibit a multiprotein complex that includes APC, Axin, and the kinase GSK3 .

Under normal circumstances, this complex is responsible for degrading the free cytosolic pool of catenin via phosphorylation of specific serine and threonine residues on the N terminal, which ultimately targets the protein for ubiquitination and proteolysis. When Inhibitors,Modulators,Libraries this complex is dissociated Inhibitors,Modulators,Libraries as a result of Wnt signaling, catenin is less efficiently phos phorylated and ubiquitinated, which leads to increase nuclear catenin levels. In the nucleus, catenin forms a complex with the TCF LEF1 family of HMG box transcrip tion factors and stimulates the expression of specific target genes including the cyclin D1 oncogene. Secreted frizzled related proteins are a family of Wnt antagonists which contain a cysteine rich domain that is homologous to the Wnt binding domain of friz zled receptor proteins.

However, SFRPs do not contain a transmembrane domain Inhibitors,Modulators,Libraries and therefore reside in the extracellular compartment where they antagonize Wnt signaling by binding to Wnt ligands and prevent ligand receptor interactions and signal transduction. Loss of SFRP expression is found in a multitude of cancers includ ing breast cancer, cervical cancer, hepatocellu lar cancer, urothelial cancer, head and neck squamous cell cancer, lymphocytic leukemia, lung cancer, neuroectodermal cancer, bladder cancer, ovarian cancer, mesothelioma, endometrial cancer, and cervical cancer. SFRP1 is a member of this protein family that is signifi cantly downregulated in breast tumors and in breast carci noma cell lines.

Moreover, loss of SFRP1 expression is associated with Inhibitors,Modulators,Libraries poor overall survival in patients with early breast cancer. The loss of SFRP1 expression occurs both at the RNA level as demonstrated by in situ hybridization and at the protein level as Inhibitors,Modulators,Libraries shown by immunohistochemistry. Recent data have revealed that like many of the cancers described above, promoter hypermethylation is the reason for selleck loss of SFRP1 mRNA and protein expression. Currently, it is unknown whether SFRP1 loss causes the mammary gland to be predisposed to breast cancer devel opment.