title: Epigenetic inactivation of the HOXA gene cluster in breast cancer.
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.
authors.affiliation: Arizona Cancer Center, Department of Pharmacology and Toxicology, Arizona Respiratory Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.forename: Taylor
authors.initials: T
authors.lastname: Jensen
authors.forename: Marc M
authors.initials: MM
authors.lastname: Oshiro
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Wozniak
authors.forename: Marcella
authors.initials: M
authors.lastname: Nouzova
authors.forename: George S
authors.initials: GS
authors.lastname: Watts
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
authors.forename: Christina
authors.initials: C
authors.lastname: Kim
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Futscher
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D005810:Multigene Family
chemical_list: D018398:Homeodomain Proteins; C088144:HoxA protein