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

Abstract

BackgroundThe 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.MethodsThe 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.ResultsMice 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.ConclusionDeletion 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5109-8) contains supplementary material, which is available to authorized users.

The Oncogenic Potential of the Centromeric Border Protein FAM84B of the 8q24.21 Gene Desert

“…For instance, FAM84B and Myc may interact via lnRNAs within the 8q24.21 gene desert. This possibility is in accordance with the co-downregulation of both genes in mice with knockout of a 430Kb fragment within the gene desert [103]. Direct interactions between FAM84B and Myc at both the protein and transcriptional levels are also possible, and the latter is intriguing in view of Myc being a transcriptional factor [109].…”

“…Its functional and genetic linkage with Myc would suggest a co-regulatory pattern with Myc. In support of this possibility, mice deficient in the 430kb region encompassing CCAT1, POU5F1B, CCAT2, and CASC8 within the 8q24.21 gene desert ( Figure 1) downregulate both FAM84B and Myc expression in mammary gland and prostate [103]. Deletion of this region delays the growth of luminal, Her2, and basal breast cancer in MMTV-PuVT, MMTV-Neu, and C3(1)-TAg transgenic mouse models for breast cancer, respectively [103].…”

“…Furthermore, among 35 cancer types within the cBioPortal database, 20 cancer types show co-amplification of FAM84B and Myc with the rate ≥5%. Ovarian cancer and breast cancer are the first (>40%) and fifth (>20%) cancer type with respect to the prevalence of FAM84B and Myc co-amplification [103]. This co-amplification associates with poor overall survival in breast cancer [103].…”

“…The co-amplification has also been detected in acute myeloid leukemia [104], esophageal cancer [105], colorectal carcinoma [106], and prostate cancer [103]. For prostate cancer (PC), we have analyzed gene amplification for Myc and FAM84B in all independent published datasets (n = 12) containing 3546 patients within cBioPortal (http://www.cbioportal.org/) [107,108] (Figure 4A).…”

Preventing cancer by long-term partial Myc suppression

“…Remarkably, wholesale germline deletion of many of these evolutionarily conserved cancerpredisposing regulatory elements markedly decreases incidence of their associated cancers yet has little impact on mouse development or adult tissue physiology 17,25,27,28 . In many, but not all, instances the observed cancer protection correlates with reduced basal levels of Myc expression in the affected organ 17 .…”