Novel roles of the inflammatory cytokine Oncostatin-M in breast cancer pathogenesis




West, Nathaniel R.

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Despite ongoing advancement in detection and treatment, breast cancer remains a major clinical challenge worldwide. Cancer has traditionally been conceptualized as a ‘disease of the genes’ by virtue of the mutagenic events necessary for its inception. It is now clear, however, that complex interactions take place between cancer cells and the array of non-cancerous cells and molecules in their immediate surroundings, known generally as the tumour microenvironment. Cancer-microenvironment interactions are increasingly recognized as processes that critically influence the outcome of disease. Cells of the host immune system are major components of the breast tumour microenvironment. While their presence in tumours is thought to reflect an attempt at disease eradication or containment, cancer cells can exploit the immune system through a variety of means, including the recognition of leukocyte-derived cytokines. As such, intratumoral leukocytes and high cytokine content are frequently associated with aggressive subtypes of breast cancer and poor prognosis. This dissertation explores the influence of one such cytokine, oncostatin-M (OSM), on the behaviour of breast cancer cells. Our results collectively demonstrate that OSM can rapidly and potently induce aggressive features in well-characterized cell models of luminal, well-differentiated breast cancer. These features include suppression of the important biomarker estrogen receptor-α (the key molecular target of endocrine therapy), gain of the breast cancer oncogene S100A7, loss of luminal epithelial differentiation and gain of mesenchymal features, and induction of a phenotype consistent with breast cancer stem cells. Each of these changes can potentially influence treatment responsiveness, the metastatic process, or both. Along with high levels of intratumoural leukocytes, the OSM-induced features listed above are known to associate with one another in human breast cancer. Tumours that display such characteristics have a poor prognosis and present the greatest challenges for modern breast cancer therapy, both because they are inherently prone to rapid metastasis and because targeted therapies for such tumours are lacking. The etiology of these aggressive disease subsets is largely unknown, and resolution of this issue would represent a major advancement in our understanding of breast cancer. Importantly, we found that expression of OSM and/or its receptor OSMR was reproducibly associated with these features in multiple breast cancer cohorts, largely confirming our experimental results. OSMR, in particular, was associated with poor clinical outcome. OSM signalling may thus provide a novel mechanistic explanation for the development of aggressive forms of breast cancer. If our findings are validated and expanded upon in future studies, OSM signalling could serve as a novel therapeutic target and may be an important consideration in the design and deployment of breast cancer immunotherapies.



breast cancer, inflammation, cytokines, oncostatin-M