Seminari de Recerca "miR-424/503 modulates Wnt/β-catenin signaling in the mammary epithelium by targeting LRP6"

Dr. Ruth Rodríguez Barrueco, Principal Investigator, Molecular Oncology Center, Oncologic Research Institute - Bellvitge Biomedical Research Institute-IDIBELL

Breast cancer is the most frequently diagnosed tumor among women, and the leading cause of female cancer death. Mammographic screening coupled with improved treatments have led to a striking increase of survival in both early and advanced settings. However, most patients presenting advanced disease will eventually progress, with more than 90% of the patients dying from metastatic breast cancer. Tumor progression and metastatic spread require high cell plasticity to quickly adapt to new scenarios and escape the immune system. Cellular metabolism largely influences the promotion and maintenance of stemness in breast cancer. The specific events, and the mechanisms by which they are controlled, require further exploration.
Previous work of our laboratory demonstrated that decreased levels of the cluster of miRNAs 424(322)/503 induce stem characteristics to normal mammary cells. Accordingly, we have recently reported that the miR-424(322)/302 cluster is a novel modulator of canonical Wnt signaling in the mammary epithelium that exerts its function by decreasing the expression of the LRP6 co-receptor. Moreover, the cluster is required for Wnt-mediated MaSC expansion induced by the ovarian cycles. 
In the context of breast cancer, the suppression of the expression of these two miRNAs in a murine model promotes hyperplasia in the mammary glands and multifocal thickening of the TDLUs (Terminal Ductal Lobular Units). We have also described that the cluster of mi-R-424(322)/503 is deleted in a group of aggressive breast tumors and reported that miR-424(322)/503 knockout mice develop mammary tumors over time which are promoted by pregnancy. These are undifferentiated tumors that resist to chemotherapeutic agents thanks to the increased expression of their target genes BCL-2 and IGF1R. We have also associated the loss of expression of miR-424(322)/503 to the acquisition of plasticity necessary to switch amongst stages and to the rewiring of major energy-producing pathways. Mechanistically, miR-424(322)/503 regulates pluripotency and metabolism via direct targeting of zinc finger protein 217 (ZNF217). Repression of this transcription factor was sufficient to reverse the stem-like and metabolic phenotypes revealing a new role of ZNF217 in mammary epithelial cells and opening the avenue to new targeted therapies for aggressive breast tumors. 

Host: Dr. Miquel Segura, Senior researcher Childhood Cancer and Blood Disorders (VHIR)