Abstract
IntroductionTriple Negative (TN) breast tumours have poor prognosis, lack of targeted therapies and are often refractory to conventional chemotherapy treatments. Therefore, finding new therapeutic targets for those tumours is an unmet need with high clinical impact. In this context, Oncostatin M receptor (OSMR) is a promising therapeutic target as it is over-expressed in this tumour subtype and its activation promotes invasiveness. We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis1,2,3. We now investigate the role of OSMR in TN breast cancer.1. Caffarel MM, Coleman N. (2014) Journal of Pathology 232:386–90.2. Kucia-Tran, et al. (2016) Brit J Cancer 115:212–222.3. Caffarel MM, et al (2013) Journal of Pathology 231:168–79.Material and methodsTo address this issue we use a wide array of tools including clinical samples, in vivo models and in vitro cell cultures of breast cancer cell lines. The expression of OSMR pathway was analysed in FFPE samples and large datasets of publicly available breast cancer samples (METABRIC, n=1462; and TCGA, n=547). The role of OSMR in oncogenesis and metastasis was studied in vivo in orthotopic xenografts of human (MDA-MB-231) and murine (4 T1) triple negative breast cancer cells in nude or syngeneic immunocompetent mice respectively.Results and discussionsOSMR and its ligand Oncostatin M (OSM) are over-expressed in basal tumours, where they associate with shorter overall survival (p=0.015). While the main source of the ligand OSM seems to be the tumour stroma, the receptor OSMR is expressed by breast cancer cells. OSM treatment induces the expression of important mediators of angiogenesis and invasion (e.g. Snail, VEGF and integrins) in TN breast cancer cells. Importantly, OSMR activation accelerates tumour onset, tumour growth and metastasis in animal models.ConclusionOur results support that OSMR pathway may have an important role in the initiation and progression of this subtype of breast cancer. OSM:OSMR interactions could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer. Therefore, OSMR pathway could be a promising candidate for therapeutic targeting.
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