RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes

// Maria Sol Recouvreux 1, 6 , Esteban Nicolas Grasso 1, 7 , Pablo Christian Echeverria 5 , Luciana Rocha-Viegas 1, 2 , Lucio Hernan Castilla 4 , Carolina Schere-Levy 1 , Johanna Melisa Tocci 1 , Edith Claudia Kordon 1, 3 , Natalia Rubinstein 1, 2 1 Instituto de Fisiologia, Biologia Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Buenos Aires, Argentina 2 Departamento de Fisiologia y Biologia Molecular y Celular, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina 3 Departamento de Quimica Biologica, UBA, Buenos Aires, Argentina 4 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA 5 Department of Biologie Cellulaire, Universite de Geneve Sciences III, Geneve, Switzerland 6 Present Address: Oncology Institute “Angel H Roffo”, Buenos Aires, Argentina 7 Present Address: Immunopharmacology Laboratory, IQUIBICEN-CONICET, FCEN-UBA, Buenos Aires, Argentina Correspondence to: Natalia Rubinstein, e-mail: nrubinstein@fbmc.fcen.uba.ar Keywords: Runx1, Foxp3, Rspo3, GJA1, gene expression regulation Received: June 08, 2015      Accepted: November 28, 2015      Published: December 28, 2015 ABSTRACT Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability.