Comparative epigenomics of human and mouse mammary tumors

Berna Demircan, Lisa M. Dyer, Mallory Gerace, Edward K. Lobenhofer, Keith D Robertson, Kevin D. Brown

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Gene silencing by aberrant epigenetic chromatin alteration is a well-recognized event contributing to tumorigenesis. Although genetically engineered tumor-prone mouse models have proven a powerful tool in understanding many aspects of carcinogenesis, to date few studies have focused on epigenetic alterations in mouse tumors. To uncover epigenetically silenced tumor suppressor genes (TSGs) in mouse mammary tumor cells, we conducted initial genome-wide screening by combining the treatment of cultured cells with the DNA demethylating drug 5-aza-2'-deoxycytidine (5-azadC) and the histone deacetylase inhibitor trichostatin A (TSA) with expression microarray. By conducting this initial screen on EMT6 cells and applying protein function and genomic structure criteria to genes identified as upregulated in response to 5-azadC/TSA, we were able to identify two characterized breast cancer TSGs (Timp3 and Rprm) and four putative TSGs (AtplB2, Dusp2, FoxJl and Smpd3) silenced in this line. By testing a panel of 10 mouse mammary tumor lines, we determined that each of these genes is commonly hypermethylated, albeit with varying frequency. Furthermore, by examining a panel of human breast tumor lines and primary tumors we observed that the human orthologs of ATPIB2, FOXJl and SMPD3 are aberrantly hypermethylated in the human disease whereas DUSP2 was not hypermethylated in primary breast tumors. Finally, we examined hypermethylation of several genes targeted for epigenetic silencing in human breast tumors in our panel of 10 mouse mammary tumor lines. We observed that the orthologs of Cdhl, RarB, Gstpl, RassFI genes were hypermethylated, whereas neither Dapkl nor Wifl were aberrantly methylated in this panel of mouse tumor lines. From this study, we conclude that there is significant, but not absolute, overlap in the epigenome of human and mouse mammary tumors.

Original languageEnglish (US)
Pages (from-to)83-97
Number of pages15
JournalGenes Chromosomes and Cancer
Volume48
Issue number1
DOIs
StatePublished - Jan 2009
Externally publishedYes

Fingerprint

Epigenomics
Breast Neoplasms
decitabine
Tumor Suppressor Genes
trichostatin A
Genes
Neoplasms
Carcinogenesis
Histone Deacetylase Inhibitors
Gene Silencing
Chromatin
Cultured Cells
Genome
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

Demircan, B., Dyer, L. M., Gerace, M., Lobenhofer, E. K., Robertson, K. D., & Brown, K. D. (2009). Comparative epigenomics of human and mouse mammary tumors. Genes Chromosomes and Cancer, 48(1), 83-97. https://doi.org/10.1002/gcc.20620

Comparative epigenomics of human and mouse mammary tumors. / Demircan, Berna; Dyer, Lisa M.; Gerace, Mallory; Lobenhofer, Edward K.; Robertson, Keith D; Brown, Kevin D.

In: Genes Chromosomes and Cancer, Vol. 48, No. 1, 01.2009, p. 83-97.

Research output: Contribution to journalArticle

Demircan, B, Dyer, LM, Gerace, M, Lobenhofer, EK, Robertson, KD & Brown, KD 2009, 'Comparative epigenomics of human and mouse mammary tumors', Genes Chromosomes and Cancer, vol. 48, no. 1, pp. 83-97. https://doi.org/10.1002/gcc.20620
Demircan, Berna ; Dyer, Lisa M. ; Gerace, Mallory ; Lobenhofer, Edward K. ; Robertson, Keith D ; Brown, Kevin D. / Comparative epigenomics of human and mouse mammary tumors. In: Genes Chromosomes and Cancer. 2009 ; Vol. 48, No. 1. pp. 83-97.
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