title: Runx2 is a novel regulator of mammary epithelial cell fate in development and breast cancer.
abstract: Regulators of differentiated cell fate can offer targets for managing cancer development and progression. Here, we identify Runx2 as a new regulator of epithelial cell fate in mammary gland development and breast cancer. Runx2 is expressed in the epithelium of pregnant mice in a strict temporally and hormonally regulated manner. During pregnancy, Runx2 genetic deletion impaired alveolar differentiation in a manner that disrupted alveolar progenitor cell populations. Conversely, exogenous transgenic expression of Runx2 in mammary epithelial cells blocked milk production, suggesting that the decrease in endogenous Runx2 observed late in pregnancy is necessary for full differentiation. In addition, overexpression of Runx2 drove epithelial-to-mesenchymal transition-like changes in normal mammary epithelial cells, whereas Runx2 deletion in basal breast cancer cells inhibited cellular phenotypes associated with tumorigenesis. Notably, loss of Runx2 expression increased tumor latency and enhanced overall survival in a mouse model of breast cancer, with Runx2-deficient tumors exhibiting reduced cell proliferation. Together, our results establish a previously unreported function for Runx2 in breast cancer that may offer a novel generalized route for therapeutic interventions. Cancer Res; 74(18); 5277-86. ©2014 AACR.
authors: Discipline of Physiology & Bosch Institute, School of Medical Sciences, The University of Sydney, NSW 2006, Australia.
authors: Thomas W
authors: TW
authors: Owens
authors: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors: Renee L
authors: RL
authors: Rogers
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.
authors: Sarah
authors: S
authors: Best
authors: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
authors: Anita
authors: A
authors: Ledger
authors: Discipline of Physiology & Bosch Institute, School of Medical Sciences, The University of Sydney, NSW 2006, Australia.
authors: Anne-Marie
authors: AM
authors: Mooney
authors: Discipline of Physiology & Bosch Institute, School of Medical Sciences, The University of Sydney, NSW 2006, Australia.
authors: Alison
authors: A
authors: Ferguson
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Paul
authors: P
authors: Shore
authors: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia.
authors: Alexander
authors: A
authors: Swarbrick
authors: Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, NSW 2052, Australia.
authors: Christopher J
authors: CJ
authors: Ormandy
authors: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Herston, Queensland 4029, Australia.
authors: Peter T
authors: PT
authors: Simpson
authors: Cancer Research UK, Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors: Jason S
authors: JS
authors: Carroll
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.
authors: Jane
authors: J
authors: Visvader
authors: Discipline of Physiology & Bosch Institute, School of Medical Sciences, The University of Sydney, NSW 2006, Australia.|Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.|Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Matthew J
authors: MJ
authors: Naylor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008137:Longitudinal Studies; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse