RSPO3 IS A GLYCOPROTEIN SECRETED BY MAMMARY TUMOR CELLS THAT INDUCES WNTPATHWAY ACTIVATION AND EMT

TOCCI J; FELCHER C; GODDIO MV; CASTRO OA; COSO O.; KORDON E

Rosario

Congreso; L Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2014

SAIB

R-spondins (RSPOs) is a family of secreted proteins that have been implicated in significant processes like embryonic development, tissue differentiation and human diseases (1). They have been also postulated as potent stem cell growth factors. In addition, we and other groups have determined that RSPOs are frequently mutated in Mouse Mammary Tumor Virus (MMTV)-induced tumors, particularly RSPO3(2, 3). Our results show that mouse and human tumorigenic and nontumorigenic mammary cells express Rspo3 mRNA, but the levels are higher in basal-like cells. They secrete the protein, which associates with the extracellular matrix and/or the cell membrane, since their conditioned medium can be enriched by treatment with soluble heparin. Rspo3 treatment of non-tumorigenic mammary epithelial cells induces changes associated to epithelial-mesenchymal transition (EMT). In addition, down-regulation of its expression in cultured basal mammary cancer cells causes inhibition of migration, vimentin expression and repression of the canonical WNT signalling pathway. When transplanted into mice, these RSPO3-KO cells resulted less tumorigenic than control cells. Our results indicate that RSPO3 is a potent oncogene, which promotes cancer development through WNT-pathway activation in mammary epithelial cells.