ß1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli

Integrins are cell adhesion receptors which mediate interactions between the extracellular matrix and the actin cytoskeleton. They are heterodimers composed of α and β subunits. As adhesion receptors, integrins are important for cell-cell and cell-matrix interactions and therefore are essential for the structural integrity of an organ. Moreover, integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. β1 integrin is the most widely expressed integrin and controls various developmental processes, including neurogenesis, chondrogenesis, skin and hair follicle morphogenesis, and myoblast fusion. To determine the role of β1 integrin in normal development of the mouse mammary gland, with a particular emphasis on how β1 integrins influcence proliferation, differentiation and apoptosis; we examined the consequence of conditional deletion of β1 integrin in mammary epithelia. Itgβ1flox/flox mice were crossed with WAPiCre transgenic mice, which led to specific ablation of β1 integrin in luminal alveolar epithelial cells. In the β1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in β1 integrin mutant glands, which correlated with a specific increase of p21Cip1 expression. In a p21Cip1 null background, there was a partial rescue of the proliferation defect, as measured by incorporation of Bromodeoxyuridene into S-phase cells. These data provide in vivo evidence linking p21Cip1 to the proliferative defect observed in β1 integrin mutant glands. A connection between p21Cip1 and β1 integrin as well as focal adhesion kinase was also established in primary mammary cells and an established cell line. Finally, transplanted mammary tissue from β1 integrin mutant females failed to repopulate recipient mammary glands, suggesting for the first time that β1 integrin may be required for the maintenance of mammary progenitor cells. Overall, we found β1 integrin has multiple roles in mouse mammary gland development. Ablation of β1 integrin in luminal alveolar cells affects proliferation at early lactation, and the integrity of alveolar lumen structures during lactation. The results also suggest that β1 integrins are necessary for mammary progenitor cell proliferation and/or survival during mammary gland remodeling.