|Title||Epigenetic inactivation of the HOXA gene cluster in breast cancer.|
|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Novak P, Jensen T, Oshiro MM, Wozniak RJ, Nouzova M, Watts GS, Klimecki WT, Kim C, Futscher BW|
|Date Published||2006 Nov 15|
|Keywords||Breast Neoplasms, Cell Line, Tumor, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Silencing, Homeodomain Proteins, Humans, Multigene Family|
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.
|Alternate Journal||Cancer Res.|
|Grant List||P30 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
Epigenetic inactivation of the HOXA gene cluster in breast cancer.
Faculty Member Reference:
George Watts, Ph.D.