Researchers from the University Hospital Basel, Switzerland showed cancer site specific phenotypes and increased glucocorticoid receptor activity in distant metastases. In patient-derived xenograft models of breast cancer in mice, an increase in stress hormones during progression or treatment with their synthetic derivatives activates the glucocorticoid receptor, and results in increased metastatic colonization and reduced survival. The findings are published on 13 March 2019 in the Nature.
The authors wrote in study background that mechanisms of metastatic colonization are poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intrapatient tumour heterogeneity and metastasis is needed.
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.
The study was based on using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice.
The study team showed 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.
Furthermore, 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.
Overall, these results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis. From clinical perspective, the authors interpreted their findings at the way that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.
Obradović MMS, Hamelin B, Manevski N, et al. Glucocorticoids promote breast cancer metastasis. Nature 2019; 567:540-544.