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.
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Authors | Nathan R West, Leigh C Murphy, Peter H Watson |
Journal | Endocrine-related cancer
(Endocr Relat Cancer)
Vol. 19
Issue 2
Pg. 181-95
(Apr 2012)
ISSN: 1479-6821 [Electronic] England |
PMID | 22267707
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- ESR1 protein, human
- Estrogen Receptor alpha
- Oncostatin M Receptor beta Subunit
- RNA, Neoplasm
- Oncostatin M
- Mitogen-Activated Protein Kinases
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Topics |
- Blotting, Western
- Breast Neoplasms
(genetics, metabolism)
- Cell Line, Tumor
- Cohort Studies
- Down-Regulation
- Estrogen Receptor alpha
(antagonists & inhibitors, biosynthesis, genetics, metabolism)
- Female
- Humans
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors, metabolism)
- Multivariate Analysis
- Neoplasms, Hormone-Dependent
(genetics, metabolism)
- Oligonucleotide Array Sequence Analysis
- Oncostatin M
(genetics, metabolism)
- Oncostatin M Receptor beta Subunit
(genetics, metabolism)
- Prognosis
- RNA, Neoplasm
(chemistry, genetics)
- Reverse Transcriptase Polymerase Chain Reaction
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