tenin signaling, up-regulation of Cyclin D1 and c-Myc expression levels, and increases the expression of the cell proliferation marker Ki67, all of which we observed experimentally in MMTV-LRP6 mice. As such, these events could account for mammary hyperplasia in MMTV-LRP6 mice.

MMPs are multifunctional enzymes capable of targeting the extracellular matrix, growth factors, cytokines and cell surface-associated adhesion and signaling receptors. Clinically, MMPs have been associated with advanced-stage cancer and contribute to tumor progression, invasion, and metastasis. In ductal breast carcinomas, it has been demonstrated that MMP-2, -3, -9, -11, -13 and -14 are synthesized either by stromal fibroblasts, infiltrating macrophages or vascular pericytes ([@R50]; [@R35]; [@R15]; [@R31] & [@R32]; [@R8]). In animal models, it has been found that expression of an autoactivating form of MMP-3 under the control of the whey acidic protein promoter induces premalignant and malignant lesions in the mammary glands. Moreover overexpression of a natural inhibitor of MMPs, tissue inhibitor of MMP (TIMP)-1, inhibits tumor formation in MMP-3 transgenic mice ([@R40]). More interestingly, Blavier et al. recently reported that the expression of several MMPs including MMP-2, -3, -9,-13, and -14 was increased in hyperplastic glands and mammary tumors of MMTV-Wnt1 transgenic mice. Furthermore, when MMTV-Wnt1 mice were crossed with transgenic mice overexpressing a natural MMP inhibitor, TIMP2, in the mammary gland, the double transgenic mice displayed an increase in tumor latency and a reduction in tumor formation ([@R5]). MMP-2, -3, -7, -9, -13 and -14 are all known target genes of the Wnt/β-catenin pathway ([@R9]; [@R41]; [@R43]; [@R51]). In the present study, we demonstrated that mammary glands from MMTV-LRP6 transgenic mice exhibit significantly higher levels of MMPs than WT littermate controls. Therefore, upregulation of MMPs could also account for mammary hyperplasia in MMTV-LRP6 mice.

Whole mount staining of mammary gland is a w