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Glucocorticoids promote breast cancer metastasis
- Source :
- Nature
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Lung Neoplasms
Tumour heterogeneity
TUMOR HETEROGENEITY
INHIBITION
Breast Neoplasms
Receptor Tyrosine Kinase-like Orphan Receptors
Dexamethasone
Metastasis
PATHWAY
03 medical and health sciences
Mice
0302 clinical medicine
Glucocorticoid receptor
Breast cancer
Receptors, Glucocorticoid
Cell Line, Tumor
REVEALS
Medicine
Animals
Humans
Neoplasm Metastasis
Receptor
Survival rate
Glucocorticoids
Mice, Inbred BALB C
Multidisciplinary
RECEPTOR
business.industry
WOMEN
QUANTIFICATION
medicine.disease
3. Good health
Survival Rate
030104 developmental biology
317 Pharmacy
030220 oncology & carcinogenesis
ROR1
Cancer research
Disease Progression
GROWTH
Female
3111 Biomedicine
business
GENOMICS
Protein Kinases
Hormone
Signal Transduction
Subjects
Details
- ISSN :
- 14764687
- Volume :
- 567
- Issue :
- 7749
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....aa50aba1c4f2794d36273fecda7bf005