Specific ß-containing integrins exert differential control on proliferation and two-dimensional collective cell migration in mammary epithelial cells.

ABSTRACT

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 ß1-integrin gene from primary cultures of mammary epithelial cells in situ, using CreER. Upon ß1-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 ß3-integrin in ß1-integrin-null cells, indicating that integrins containing different ß-subunits exert differential control on mammary epithelial proliferation and migration. ß1-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 ß1-integrin-depleted cells, indicating that this GTPase is essential in propagating proliferative ß1-integrin signals. These results show that ß1-integrins promote cell cycle in mammary epithelial cells, whereas ß3-integrins are involved in migration.