IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
B catenin contribution to breast tumor progression
Autor/es:
NATALIA RUBINSTEIN.; MEERA SAXENA; DAVID BÜCHEL; TOMAS VALENTA; KONRAD BASLER; GERHARD CHRISTOFORI
Lugar:
Bariloche
Reunión:
Congreso; SISTAM, Third South American Spring Symposium in Signal Transduction and Molecular Medicine; 2015
Resumen:
The Wnt/β-catenin signal pathway has been widely explored in different tumor models. β-catenin (β) is a protein of dual action. Is able to translocate to the nucleus regulating gene expression and also an important component in the cadherin-based cell-cell adhesion system. The main goal of this work was to explore the differential contribution of the different parts and functions of β in breast tumor generation, progression and metastasis. To analyse this we develop three experimental in vivo models combining β knockout (KO) mice with mutant β knockin (KI) mice, using Polyomavirus middle T-antigen (PyMT) as tumor model inducer. To test the participation of full wild type β on tumor progression we generate conditional KO mice (βcat fl/fl; MMTV-CRE+/-; PyMT+/-). We found no difference in tumor growth and lung metastasis incidence compared to control. Tumor DNA-PCR analysis and β immunofluorescence assays showed low levels of β gene deletion. To evaluate this phenomenon we generate primary tumor cell lines MMTV-Cre-/- and transduced them with Adenovirus-CRE-ires-GFP. After 72h β gene deletion induced apoptosis in these cells. To investigate nuclear β contribution to tumor progression without altering β adherent properties we generate: a KI mouse containing mutant βcat (DA) unable to bind Bcl9/L (βcat fl/DA; MMTV-CRE+/-) and a KI mouse containing mutant βcat with C-terminal deletion unable to bind specific co-factors (βcatfl/DC; MMTV-CRE+/-). Both mutations significantly reduce tumor growth and DA also significantly reduces lung metastasis. Besides, both mutations work as dominant negative over wild type βcat. These results suggest that βcat contributes in a differential way to breast tumor growth in vivo. Full βcat is necessary for tumor epithelial cell survival while tumor progression and lung metastasis depends on Bcl9/L and co-factors interactions important in the regulation of target genes.