Epigenetic inactivation of the HOXA gene cluster in breast cancer.

TitleEpigenetic inactivation of the HOXA gene cluster in breast cancer.
Publication TypeJournal Article
Year of Publication2006
AuthorsNovak P, Jensen T, Oshiro MM, Wozniak RJ, Nouzova M, Watts GS, Klimecki WT, Kim C, Futscher BW
JournalCancer Res
Volume66
Issue22
Pagination10664-70
Date Published2006 Nov 15
ISSN0008-5472
KeywordsBreast Neoplasms, Cell Line, Tumor, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Homeodomain Proteins, Humans, Multigene Family
Abstract

Using an integrated approach of epigenomic scanning and gene expression profiling, we found aberrant methylation and epigenetic silencing of a small neighborhood of contiguous genes-the HOXA gene cluster in human breast cancer. The observed transcriptional repression was localized to approximately 100 kb of the HOXA gene cluster and did not extend to genes located upstream or downstream of the cluster. Bisulfite sequencing, chromatin immunoprecipitation, and quantitative reverse transcription-PCR analysis confirmed that the loss of expression of the HOXA gene cluster in human breast cancer is closely linked to aberrant DNA methylation and loss of permissive histone modifications in the region. Pharmacologic manipulations showed the importance of these aberrant epigenetic changes in gene silencing and support the hypothesis that aberrant DNA methylation is dominant to histone hypoacetylation. Overall, these data suggest that inactivation of the HOXA gene cluster in breast cancer may represent a new type of genomic lesion-epigenetic microdeletion. We predict that epigenetic microdeletions are common in human cancer and that they functionally resemble genetic microdeletions but are defined by epigenetic inactivation and transcriptional silencing of a relatively small set of contiguous genes along a chromosome, and that this type of genomic lesion is metastable and reversible in a classic epigenetic fashion.

DOI10.1158/0008-5472.CAN-06-2761
Alternate JournalCancer Res.
PubMed ID17090521
Grant ListP30 CA023074 / CA / NCI NIH HHS / United States
P30CA023074 / CA / NCI NIH HHS / United States
P30ES06694 / ES / NIEHS NIH HHS / United States
R33CA091351 / CA / NCI NIH HHS / United States
P30 ES006694 / ES / NIEHS NIH HHS / United States
CA09213 / CA / NCI NIH HHS / United States
R01CA65662 / CA / NCI NIH HHS / United States
ES007091 / ES / NIEHS NIH HHS / United States
Faculty Member Reference: 
George Watts, Ph.D.