Specific β-containing Integrins Exert Differential Control on Proliferation and Two-dimensional Collective Cell Migration in Mammary Epithelial Cells

Understanding how cell cycle is regulated in normal mammary epithelia is essential for deciphering defects of breast cancer and therefore for developing new therapies. Signals provided by both the extracellular matrix and growth factors are essential for epithelial cell proliferation. However, the mechanisms by which adhesion controls cell cycle in normal epithelia are poorly established. In this study, we describe the consequences of removing the beta 1-integrin gene from primary cultures of mammary epithelial cells in situ, using CreER. Upon beta 1-integrin gene deletion, the cells were unable to progress efficiently through S-phase, but were still able to undergo collective two-dimensional migration. These responses are explained by the presence of beta 3-integrin in beta 1-integrin-null cells, indicating that integrins containing different beta-subunits exert differential control on mammary epithelial proliferation and migration. beta 1-Integrin deletion did not inhibit growth factor signaling to Erk or prevent the recruitment of core adhesome components to focal adhesions. Instead the S-phase arrest resulted from defective Rac activation and Erk translocation to the nucleus. Rac inhibition prevented Erk translocation and blocked proliferation. Activated Rac1 rescued the proliferation defect in beta 1-integrin-depleted cells, indicating that this GTPase is essential in propagating proliferative beta 1-integrin signals. These results show that beta 1-integrins promote cell cycle in mammary epithelial cells, whereas beta 3-integrins are involved in migration.