Abstract A06: The murine ortholog of the human cancer-associated 8q24 gene desert affects mammary tumorigenesis and alters mammary gland development through Myc-mediated global gene expression regulation

The vast majority of breast cancer-associated variants identified by genome-wide association studies (GWAS) are located to non-protein coding genomic regions. Although some have been shown to regulate the expression of specific genes, novel approaches to elucidate the in vivo mechanisms underlying such breast cancer susceptibility loci are needed. The gene desert located on human chromosomal band 8q24, proximal to MYC and PVT1, and distal to FAM84B, harbors 2 common, low-penetrance breast cancer variants. We generated a megadeletion mouse model lacking 430 Kb of sequence orthologous to the breast cancer-associated locus of the 8q24 gene desert. Homozygous megadeletion mice are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. We found that the mutation altered mammary gland development, resulting in less branch points, terminal end buds and altered luminal/basal ratio. Using a reciprocal mammary gland transplantation assay, we found a strong donor effect and weaker host effect of the mutation on mammary gland development, indicating that the non-protein coding locus affects mammary cell-autonomous as well as non-mammary cell-autonomous processes. When crossed to the PyVT mouse model for luminal breast cancer and the C3(1)-TAg mouse model for basal breast cancer, we found that the mutation in homozygous state increased latency in both models, but stronger in the PyVT model. This finding is consi...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Animal Models: Poster Presentations - Proffered Abstracts Source Type: research