Glucocorticoid receptor (GR) activity increases at distant metastatic sites in breast cancer.
Major finding: Glucocorticoid receptor (GR) activity increases at distant metastatic sites in breast cancer.
Concept: GR activity increases expression of the kinase ROR1, which drives metastasis and reduces survival.
Impact: Judicious administration of corticosteroids may be required when treating cancer-related complications.
Intrapatient tumor heterogeneity within and between primary tumors and their respective metastases remains a significant obstacle to the accurate diagnosis and treatment of many cancers. Obradovic and colleagues employed multiple cell line– and patient-derived xenograft models of breast cancer to explore the signaling mechanisms involved in metastasis. Following implantation and subsequent removal of primary tumor cells, metastases were found in lung, liver, spleen, and ovaries and in circulation. Transcriptional profiling revealed cancer cells clustered according to the site of metastasis, and pathway analysis indicated an increase in glucocorticoid receptor (GR) activity in metastases compared with primary tumors. Additionally, plasma levels of the stress hormones cortisol, corticosterone, and adrenocorticotropic hormone were higher in mice with metastases versus healthy control mice or mice with tumors but no metastases. Proteomic analysis from GR-activated cells revealed increased levels of kinases related to GR activation, including ROR1. In vivo, ROR1 levels were higher in metastases versus matched primary tumors, and a publicly available dataset of distant breast cancer metastases showed a significant positive correlation between ROR1 mRNA levels and a GR activation signature. In vitro activation of GR by dexamethasone increased the colonization capacity of multiple cell lines, and in vivo activation of GR after tumor implantation enhanced metastasis formation and reduced overall survival. Conversely, depletion of ROR1 in these models decreased colonization capacity and prolonged survival. These data indicate that increase of GR activity in breast cancer leads to upregulation of ROR1, which drives metastasis. These results also suggest that caution should be exercised when administering corticosteroids to patients receiving chemotherapy or patients with advanced disease so as to prevent treatment-induced disease progression.
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