Abstract P2-07-02: A novel megadeletion mouse model for mechanistic studies on the 8q24 non-coding breast cancer susceptibility locus

Abstract

Abstract Genome-wide association studies (GWAS) have identified over 80 variants associated with breast cancer susceptibility. These loci have low-penetrance and are common in the population. Some of the alleles are associated with specific types of breast cancer, and/or associate differentially between certain ancestral populations. The vast majority of common, low-penetrance breast cancer susceptibility variants are located in non-protein coding genomic regions. It is hypothesized that the polymorphisms along the risk-associated alleles alter regulatory elements to modulate gene expression regulation. How such gene regulatory effects affect the susceptibility to breast cancer is completely unknown. To begin to study in vivo mechanisms underlying such non-protein coding breast cancer-associated loci, novel mammalian genetic models are indispensable. A prototype non-coding breast cancer susceptibility locus is the gene desert (i.e. a large genomic region devoid of known protein-coding genes) on human chromosomal band 8q24. The gene desert is flanked by MYC, PVT1 and FAM84b. It harbors 2 common, low-penetrance breast cancer susceptibility variants. We developed a novel megadeletion mouse model lacking a 450-Kb non-coding region orthologous to the breast cancer-associated 8q24 gene desert region. Mice homozygous for the megadeletion are viable. Analysis of the transcript levels of the flanking genes reveal organ-specific effects of the megadeletion mutation. Through genetic crosses with well-known transgenic mouse breast cancer models, we will examine the region's effect on mammary cancer multiplicity, size, latency and metastasis. Additional phenotyping and gene expression analysis will reveal novel insight in the mechanisms underlying this non-protein coding breast cancer-associated gene desert locus. The conclusions will extend beyond the 8q24 locus and will aid in understanding the influence of common, low-penetrance breast cancer loci in the etiology of breast cancer. [The mouse model was generated with help from University of Wisconsin Paul P. Carbone Comprehensive Cancer Center funds. The work is supported by a DoD MUSC-Baylor BRIDGE scholarship awarded to BMGS]. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-02.