Glucocorticoids promote breast cancer metastasis.

Autor: Obradović MMS; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Wellmera AG, Basel, Switzerland., Hamelin B; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland., Manevski N; Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.; UCB Celltech, Development Sciences, Slough, UK., Couto JP; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Sethi A; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.; Swiss Institute of Bioinformatics, Basel, Switzerland., Coissieux MM; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Münst S; Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland., Okamoto R; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Kohler H; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland., Schmidt A; Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland., Bentires-Alj M; Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland. m.bentires-alj@unibas.ch.; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. m.bentires-alj@unibas.ch.
Jazyk: angličtina
Zdroj: Nature [Nature] 2019 Mar; Vol. 567 (7749), pp. 540-544. Date of Electronic Publication: 2019 Mar 13.
DOI: 10.1038/s41586-019-1019-4
Abstrakt: Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy 1-3 . Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade 4 , 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.
Databáze: MEDLINE
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