title: Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer.
abstract: The most important clinical biomarker for breast cancer management is oestrogen receptor alpha (ERα). Tumours that express ER are candidates for endocrine therapy and are biologically less aggressive, while ER-negative tumours are largely treated with conventional chemotherapy and have a poor prognosis. Despite its significance, the mechanisms regulating ER expression are poorly understood. We hypothesised that the inflammatory cytokine oncostatin M (OSM) can downregulate ER expression in breast cancer. Recombinant OSM potently suppressed ER protein and mRNA expression in vitro in a dose- and time-dependent manner in two human ER+ breast cancer cell lines, MCF7 and T47D. This was dependent on the expression of OSM receptor beta (OSMRβ) and could be blocked by inhibition of the MEKK1/2 mitogen-activated protein kinases. ER loss was also necessary for maximal OSM-induced signal transduction and migratory activity. In vivo, high expression of OSM and OSMR mRNA (determined by RT-PCR) was associated with reduced ER (P<0.01) and progesterone receptor (P<0.05) protein levels in a cohort of 70 invasive breast cancers. High OSM and OSMR mRNA expression was also associated with low expression of ESR1 (ER, P<0.0001) and ER-regulated genes in a previously published breast cancer gene expression dataset (n=321 cases). In the latter cohort, high OSMR expression was associated with shorter recurrence-free and overall survival in univariate (P<0.0001) and multivariate (P=0.022) analyses. OSM signalling may be a novel factor causing suppression of ER and disease progression in breast cancer.
authors.affiliation: Deeley Research Centre, BC Cancer Agency, Victoria, British Columbia, Canada.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: West
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Murphy
authors.forename: Peter H
authors.initials: PH
authors.lastname: Watson
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015999:Multivariate Analysis; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D053683:Oncostatin M / Q000235:genetics / Q000378:metabolism*; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D053681:Oncostatin M Receptor beta Subunit; D012334:RNA, Neoplasm; D053683:Oncostatin M; D020928:Mitogen-Activated Protein Kinases