WNT/beta-catenin signaling in BRCA-deficient cells
WNT/beta-catenin signaling plays key roles in normal tissue development and homeostasis, where it controls cell proliferation, differentiation and apoptosis. Deregulation of this pathway is associated with cancer progression or inhibition, depending on the genetic context. Glycogen synthase kinase 3 (GSK3), is a serine/threonine kinase which mediates WNT/beta-catenin signaling through phosphorylation and subsequent degradation of beta-catenin. Here, we demonstrate that GSK3 chemical inhibition is toxic to BRCA1/2-deficient cells, including the olaparib-resistant Brca1-/-, 53BP1-deficient cells. GSK3 inhibitors stabilise beta-catenin and trigger aberrant transcription, replication stress and DNA damage accumulation in cells lacking BRCA2. These effects are reversed by beta-catenin inactivation. Our results suggest that GSK3-dependent beta-catenin stabilization may be used for the selective targeting of cells and tumors with compromised BRCA1/2 function.
Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, U.K.
Directeur de Recherche CNRS
Domain 2 - UMR 3244 - Dynamics of genetic Information