title: Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer.
abstract: A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2'-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.
authors.affiliation: Department of Surgery and Molecular Oncology, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: G
authors.initials: G
authors.lastname: Nicoll
authors.forename: D N
authors.initials: DN
authors.lastname: Crichton
authors.forename: H E
authors.initials: HE
authors.lastname: McDowell
authors.forename: N
authors.initials: N
authors.lastname: Kernohan
authors.forename: T R
authors.initials: TR
authors.lastname: Hupp
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D019656:Loss of Heterozygosity; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; C096870:Hic1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D000077209:Decitabine; D001374:Azacitidine