title: Differential hypermethylation of SOCS genes in ovarian and breast carcinomas.
abstract: Suppressor of cytokine signaling (SOCS) proteins have emerged as critical attenuators of cytokine-mediated processes, suggesting a role in the suppression of tumorigenesis. In the ovary and mammary gland, cytokines such as prolactin and IL-6 are important regulators of growth and differentiation. We have investigated whether silencing or inactivation of SOCS genes occurs in ovarian and breast carcinomas. The SOCS1 and SOCS2 CpG islands were found to be hypermethylated in 23 and 14% of primary ovarian cancers, respectively, whereas only SOCS1 was methylated in breast cancers (9%). Methylation of these genes did not occur in normal tissues. No correlation was apparent between methylation and loss of heterozygosity, and no somatic mutations were found in a large panel of carcinomas. Aberrant methylation of these SOCS genes correlated with transcriptional silencing in ovarian and breast cancer cell lines, since expression was induced by the demethylating agent 5-azadeoxycytidine. SOCS3 was not hypermethylated in either cancer type. Consistent with this data, SOCS1 and SOCS2 but not SOCS3 suppressed the growth of ovarian and breast cancer cells. Hypermethylation and silencing of specific SOCS genes in the ovary, and to a lesser extent in breast, may augment cytokine responsiveness in these tissues, thereby contributing to oncogenesis.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: David Y H
authors.initials: DY
authors.lastname: Choong
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.forename: Luci
authors.initials: L
authors.lastname: Brentzell
authors.forename: Wayne
authors.initials: W
authors.lastname: Phillips
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors