Editors' ChoiceBreast Cancer

Metastasis: Don’t stress it!

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaax1717
DOI: 10.1126/scitranslmed.aax1717


Stress hormones promote breast cancer metastasis to lung.

Improving the treatment of metastases represents a leading edge of clinical management for patients with breast cancer. For metastases to develop, primary breast tumor cells need to evolve in order to colonize secondary sites. The “holy grail” of metastasis research is to use patient-matched primary and metastasis cells and tissue. Obradovic et al. utilized patient-derived xenografts to make such a model of primary tumors and their metastases. Using transcriptional profiling of matched tumors, they showed that increased expression of glucocorticoid receptor (GR) can lead to breast to lung metastases. Specifically, they showed that an increase in the stress hormones cortisol, corticosterone, and adrenocorticotropin hormone (ACTH) during breast cancer progression resulted in the activation of GR at lung metastasis sites and increased colonization, leading to reduced survival. Mechanistically, they found that activation of GR in breast tumors lead to increased expression of ROR1, a tyrosine-protein kinase transmembrane receptor that binds WNT5a, in lung metastases.

GR also mediates the effects of synthetic derivatives of cortisol, such as dexamethasone. Clinically, dexamethasone is used to decrease edema associated with tumors, stimulate appetite in cancer patients, and to treat nausea and vomiting associated with chemotherapy drugs. The research group showed that when tumor cells were pretreated in vitro with dexamethasone and then xenografted, resulting metastatic tumors showed a decreased response to the chemotherapy drug paclitaxel. Knockdown of ROR1 in primary breast tumor cells abrogated both growth and resistance to dexamethasone-induced paclitaxel resistance in breast cancer metastasis to the lung.

Although these findings indicate that we must look closer at the administration of glucocorticoid hormones to patients with breast cancer, they also raise several biological questions. Additional studies need to be conducted into whether GR activation is necessary for metastasis in all subtypes of breast cancer. It also remains to be determined whether the lung’s microenvironment contributes to GR-mediated breast cancer metastasis. Lastly, inhibition of ROR1 through small molecule– or chimeric antigen receptor T cell–mediated immunotherapy could potentially result in translational and clinical prevention of breast cancer to lung metastasis. Nevertheless, prior work from others has shown that chemotherapy in a preclinical model of breast cancer can induce metastasis. Taken together, we now have increasing evidence that clinically driven therapies may promote tumor spread.

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