Glucocorticoids promote breast cancer metastasis

Milan M. S. Obradović, Baptiste Hamelin, Nenad Manevski, Joana Pinto Couto, Atul Sethi, Marie-May Coissieux, Simone Münst, Ryoko Okamoto, Hubertus Kohler, Alexander Schmidt and Mohamed Bentires-Alj ()
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Milan M. S. Obradović: University Hospital Basel, University of Basel
Baptiste Hamelin: University Hospital Basel, University of Basel
Nenad Manevski: University of Helsinki
Joana Pinto Couto: University Hospital Basel, University of Basel
Atul Sethi: University Hospital Basel, University of Basel
Marie-May Coissieux: University Hospital Basel, University of Basel
Simone Münst: University Hospital Basel, University of Basel
Ryoko Okamoto: University Hospital Basel, University of Basel
Hubertus Kohler: Friedrich Miescher Institute for Biomedical Research
Alexander Schmidt: University of Basel
Mohamed Bentires-Alj: University Hospital Basel, University of Basel

Nature, 2019, vol. 567, issue 7749, 540-544

Abstract: Abstract Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy1–3. Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade4, remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.

Date: 2019
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DOI: 10.1038/s41586-019-1019-4

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