Wnt/β-catenin signaling pathway is involved in the maintenance of the progenitor cell population in the skin, intestine and other tissues, and its aberrant activation caused by stabilization of β-catenin contributes to tumorigenesis. In the mammary gland, constitutive activation of Wnt/β-catenin signaling in luminal secretory cells results in precocious lobuloalveolar differentiation and induces adenocarcinomas, whereas the impact of this signaling pathway on the function of the second major mammary epithelial cell lineage, the basal myoepithelial cells, has not been analyzed. We have used the keratin (K) 5 promoter to target the expression of stabilized N-terminally truncated β-catenin to the basal cell layer of mouse mammary epithelium. The transgenic mice presented an abnormal mammary phenotype:precocious lateral bud formation, increased proliferation and premature differentiation of luminal epithelium in pregnancy, persistent proliferation in lactation and accelerated involution. Precocious development in pregnancy was accompanied by increased Myc and cyclin D1 transcript levels, and a shift in p63 variant expression towards the ΔNp63 form. The expression of ECM-degrading proteinases and their inhibitors was altered in pregnancy and involution. Nulliparous transgenic females developed mammary hyperplasia that comprised undifferentiated basal (K5/14-positive, K8- and α-smooth muscle-actin-negative) cells. Multiparous mice, in addition, developed invasive basal-type carcinomas. Thus, activation of β-catenin signaling in basal mammary epithelial cells affects the entire process of mammary gland development and induces amplification of basal-type cells that lack lineage markers, presumably, a subpopulation of mammary progenitors able to give rise to tumors.
224 ECM = extracellular matrix; FGF2 = basic fibroblast growth factor; PTHrP = parathyroid hormone-related protein; TEB = terminal end buds. Breast Cancer Research Vol 4 No 6 Deugnier et al. IntroductionThe mammary gland consists of secretory alveoli connected by a system of branching ducts embedded in connective tissue. The epithelial cells that compose the gland are arranged in two layers, the luminal epithelial layer and the basal myoepithelial layer. The whole structure is surrounded by a basement membrane.The myoepithelial layer is organised differently in the ducts and in the lobules. In the ducts, elongated myoepithelial cells form a more or less continuous layer and are in direct contact with the basement membrane, and hence with the stroma. The interaction between ductal luminal cells and the extracellular matrix (ECM) is largely mediated by the myoepithelium, although some of the luminal cells in the mammary ducts may reach the basement membrane. Alveolar myoepithelial cells are of stellate shape and form a basket-like structure around the acini, resulting in the exposure of most of the basal surface of the luminal cell to the basement membrane. Differentiated myoepithelial cells are highly contractile and their ultrastructure is reminiscent of that of smooth muscle cells. Myoepithelial cells contain large amounts of microfilaments, dense plaques (cell-matrix adherens junctions characteristic of smooth muscle cells) and smooth muscle-specific cytoskeletal and contractile proteins. They are true epithelial cells, however, because the major components of their intermediate filament system are the cytokeratins 5 and 14 (K5 and K14), because they form desmosomes, hemidesmosomes and cadherin-mediated cell-cell junctions, and because they are permanently separated from the connective tissue by the underlying basement membrane.The contractile properties and the central role in milk ejection during lactation are the most studied aspects of mammary myoepithelial cell function. In addition, the tumour suppressor potential of mammary myoepithelial cells has recently received considerable attention. However, the role played by the myoepithelial cells in ReviewThe importance of being a myoepithelial cell AbstractThe mammary myoepithelial cell was named the 'Cinderella of mammary cell biology' in light of the earlier focus on the luminal cell. Mammary myoepithelial cells have recently been described as 'natural tumour suppressors'. We now need to understand more about their origin and to reconsider their place in the complex process of mammary morphogenesis. In the present review, we discuss the lineage segregation of mammary myoepithelial cells and their functions in mammary gland development. These functions include their effects on luminal cell growth and differentiation, their key role in the establishment of the polarised mammary epithelial bilayer and the control of stromal invasion in breast cancer.
Integrins are major extracellular matrix (ECM) receptors that can also serve for some cell-cell interactions. They have been identified as important regulators of mammary epithelial cell growth and differentiation. Their ability to promote cell anchorage, proliferation, survival, migration, and the induction of active ECM-degrading enzymes suggests that they play an essential role in normal mammary morphogenesis, but, on the other hand, reveals their potential to promote tumor progression.
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