RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes
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María Sol Recouvreux1,6, Esteban Nicolás Grasso1,7, Pablo Christian Echeverria5, Luciana Rocha-Viegas1,2, Lucio Hernán Castilla4, Carolina Schere-Levy1, Johanna Melisa Tocci1, Edith Claudia Kordon1,3, Natalia Rubinstein1,2
1Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Buenos Aires, Argentina
2Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina
3Departamento de Química Biológica, UBA, Buenos Aires, Argentina
4Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
5Department of Biologie Cellulaire, Universite de Geneve Sciences III, Geneve, Switzerland
6Present Address: Oncology Institute “Angel H Roffo”, Buenos Aires, Argentina
7Present Address: Immunopharmacology Laboratory, IQUIBICEN-CONICET, FCEN-UBA, Buenos Aires, Argentina
Natalia Rubinstein, e-mail: [email protected]
Keywords: Runx1, Foxp3, Rspo3, GJA1, gene expression regulation
Received: June 08, 2015 Accepted: November 28, 2015 Published: December 28, 2015
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.
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