title: Specific β-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 β1-integrin gene from primary cultures of mammary epithelial cells in situ, using CreER. Upon β1-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 β3-integrin in β1-integrin-null cells, indicating that integrins containing different β-subunits exert differential control on mammary epithelial proliferation and migration. β1-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 β1-integrin-depleted cells, indicating that this GTPase is essential in propagating proliferative β1-integrin signals. These results show that β1-integrins promote cell cycle in mammary epithelial cells, whereas β3-integrins are involved in migration.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Alexa I
authors.initials: AI
authors.lastname: Jeanes
authors.forename: Pengbo
authors.initials: P
authors.lastname: Wang
authors.forename: Paulina
authors.initials: P
authors.lastname: Moreno-Layseca
authors.forename: Nikki
authors.initials: N
authors.lastname: Paul
authors.forename: Julia
authors.initials: J
authors.lastname: Cheung
authors.forename: Ricky
authors.initials: R
authors.lastname: Tsang
authors.forename: Nasreen
authors.initials: N
authors.lastname: Akhtar
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Foster
authors.forename: Keith
authors.initials: K
authors.lastname: Brennan
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D019012:Integrin beta1