β1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli

Integrin - extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta 1 integrin in the mammary gland, Itg beta 1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta 1 integrin in luminal alveolar epithelial cells. In the beta 1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell - basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta 1 integrin mutant glands, which correlated with a specific increase of p21(Cip1) expression. In a p21(Cip1) null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21(Cip1) to the proliferative defect observed in beta 1 integrin mutant glands. A connection between p21(Cip1) and beta 1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta 1 integrin signaling in mammary epithelial cell proliferation.