Journal Article

Deletion of the murine ortholog of the 8q24 gene desert has anti-cancer effects in transgenic mammary cancer models

Shunkwiler, Lauren B., Garrett-Mayer, Elizabeth, Homer-Bouthiette, Collin, Smits, Bart M. G., Van Peel, Benjamine, Baird, Rachael C., Rissman, Anna I., Guest, Stephen T., Powers, Patricia A., Ethier, Stephen P., Zhao, Yang, John, Manorama C., Haag, Jill D., Gould, Michael N.

2018

Overview

Background The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. The locus, including the gene desert and its flanking genes, MYC , PVT1 and FAM84B , is also frequently amplified in human breast cancer. We generated a megadeletion (MD) mouse model lacking 430-Kb of sequence orthologous to the breast cancer-associated region in the gene desert. The goals were to examine the effect of the deletion on mammary cancer development and on transcript level regulation of the candidate genes within the locus. Methods The MD allele was engineered using the MICER system in embryonic stem cells and bred onto 3 well-characterized transgenic models for breast cancer, namely MMTV-PyVT , MMTV-neu and C3(1)-TAg. Mammary tumor growth, latency, multiplicity and metastasis were compared between homozygous MD and wild type mice carrying the transgenes. A reciprocal mammary gland transplantation assay was conducted to distinguish mammary cell-autonomous from non-mammary cell-autonomous anti-cancer effects. Gene expression analysis was done using quantitative real-time PCR. Chromatin interactions were evaluated by 3C. Gene-specific patient outcome data were analysed using the METABRIC and TCGA data sets through the cBioPortal website. Results Mice homozygous for the MD allele are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. The deletion interferes with mammary tumorigenesis in mouse models for luminal and basal breast cancer. In the MMTV-PyVT model the mammary cancer-reducing effects of the allele are mammary cell-autonomous. We found organ-specific effects on transcript level regulation, with Myc and Fam84b being downregulated in mammary gland, prostate and mammary tumor samples. Through analysis using the METABRIC and TCGA datasets, we provide evidence that MYC and FAM84B are frequently co-amplified in breast cancer, but in contrast with MYC , FAM84B is frequently overexpressed in the luminal subtype, whereas MYC activity affect basal breast cancer outcomes. Conclusion Deletion of a breast cancer-associated non-protein coding region affects mammary cancer development in 3 transgenic mouse models. We propose Myc as a candidate susceptibility gene, regulated by the gene desert locus, and a potential role for Fam84b in modifying breast cancer development.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipose tissue / Alleles / Analysis / Animal models / Animals / Biomedical and Life Sciences / Biomedicine / Body weight / Breast cancer / Breast cancer susceptibility / Cancer Research / Care and treatment / Chromatin / Chromosome 8 / Clonal deletion / Colorectal cancer / Data processing / Development and progression / Embryo cells / ErbB-2 protein / Female / Fibrocystic breast disease / Gene deletion / Gene expression / Gene Expression Regulation, Neoplastic - genetics / Gene Knockout Techniques / Gene loci / Gene regulation / Genes, myc - genetics / Genetic aspects / Genetic diversity / Genetics / Genome-wide association studies / Genomes / genomics and epigenetics / GWAS / Health aspects / Health Promotion and Disease Prevention / Health risk assessment / Laboratory rats / Lactic acid / Latency / Mammary gland / Mammary Neoplasms, Experimental - genetics / Medicine/Public Health / Membrane Proteins / Metastases / Metastasis / Mice / Mice, Transgenic / Murine / Myc protein / Neoplasm Proteins - genetics / Noncoding / Oncology / Prostate / Proteins / Research Article / Risk / Rodents / Single nucleotide polymorphisms / SNP / Stem cells / Surgical Oncology / Transcription / Transgenic mice / Treatment outcome / Tumors