title: The requirement of integrins for breast epithelial proliferation.
abstract: Epithelial cells forming mammary gland ducts and alveoli require adhesion to the extracellular matrix for their function. Mammary epithelial cells need β1-integrins for normal cell cycle regulation. However, the role of β1-integrins in tumorigenesis has not been fully resolved. β1-integrin is necessary for tumour formation in transgenic mice expressing the Polyomavirus Middle T antigen, but it is dispensable in those overexpressing ErbB2. This suggests that some oncogenes can manage without β1-integrin to proliferate and form tumours, while others still require it. Here we have developed a model to test whether expression of an oncogene can surpass the need for β1-integrin to drive proliferation. We co-expressed the ErbB2 or Akt oncogenes with shRNA to target β1-integrin in mammary epithelial cells, and found that they show a differential dependence on β1-integrin for cell division. Moreover, we identified a key proliferative role of the Rac1-Pak axis downstream of β1-integrin signalling. Our data suggest that, in mammary epithelial cells, oncogenes with the ability to signal to Pak surpass the requirement of integrins for malignant transformation. This highlights the importance of using the correct combination therapy for breast cancer, depending on the oncogenes expressed in the tumour.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: p.moreno-layseca@uke.de.
authors.forename: Paulina
authors.initials: P
authors.lastname: Moreno-Layseca
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: ahmet.ucar@manchester.ac.uk.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ucar
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: heyuan.sun@postgrad.manchester.ac.uk.
authors.forename: Heyuan
authors.initials: H
authors.lastname: Sun
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: amber.wood@postgrad.manchester.ac.uk.
authors.forename: Amber
authors.initials: A
authors.lastname: Wood
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: Safiah
authors.initials: S
authors.lastname: Olabi
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: agilmore@manchester.ac.uk.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Gilmore
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: keith.brennan@manchester.ac.uk.
authors.forename: Keith
authors.initials: K
authors.lastname: Brennan
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom. Electronic address: cstreuli@manchester.ac.uk.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D039641:Integrin beta Chains; D009479:Neuropeptides; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; C484602:Rac1 protein, mouse; C524056:Erbb2 protein, mouse
keywords: Beta1-integrin; Mammary epithelial cells; Oncogenes; Proliferation