Abstract LB-200: Loss of the scaffold protein Kibra in a mouse model of triple-negative breast cancer

Introduction: Targeted therapies in breast cancer rely on tumor cell expression of Estrogen and/or HER2 receptors. Triple negative breast cancers (TNBCs), lacking these receptors, have no targeted therapies. We have developed a preclinical murine model expressing a naturally occurring oncogenic variant of the Met receptor in the mammary gland combined with loss of function of the tumour suppressor p53 (MMTV-Met;Trp53fl/+;Cre). This model recapitulates many features of TNBC at the level of gene expression, pathological markers and genomic alterations. Notably, this model spontaneously undergoes loss of a genomic region syntenic with human chromosome 5q which is lost in up to 70% of human TNBCs (Turner et al., 2010). This provides an opportunity for us to identify and study potential driver genes for this breast cancer subtype.Experimental procedures: Approximately 80% of MMTV-Met;Trp53fl/+;Cre mammary tumors have a mesenchymal pathology that recapitulates key features of TNBC. Array CGH profiling showed a consistent loss of chromosome 11:31.35-58.2Mb, syntenic with human 5q31.1 and 5q33.1-35.3. Analysis of mouse model expression profiling data confirmed decreased expression of 83 genes within this region. Comparison with human breast cancers within the TCGA dataset further highlighted 14 of these genes with significantly decreased expression in humans with the TNBC subtypes ‘Basal’ and ‘Claudin-low’. One of these genes, WWC1, undergoes heterozygous deletion in 49% of h...

Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Knight, J. F., Gruosso, T., de Verteuil, D. A., Saleh, S., Lesurf, R., Zhao, H., Davis, R., Zuo, D., Cardiff, R., Gregg, J., Hallett, M., Park, M. Tags: Tumor Biology Source Type: research