Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase. (10th September 2019) - Flaherty, Renée L.
Abstract: Stress hormones have been shown to be important mediators in driving malignant growth and reducing treatment efficacy in breast cancer. Glucocorticoids can induce DNA damage through an inducible nitric oxide synthase (iNOS) mediated pathway to increase levels of nitric oxide (NO). Using an immune competent mouse breast cancer model and 66CL4 breast cancer cells we identified a novel role of NOS inhibition to reduce stress-induced breast cancer metastasis. On a mechanistic level we show that the glucocorticoid cortisol induces expression of keys genes associated with angiogenesis, as well as pro-tumourigenic immunomodulation. Transcriptomics analysis confirmed that in the lungs of tumour-bearing mice, stress significantly enriched pathways associated with tumourigenesis, some of which could be regulated with NOS inhibition. These results demonstrate the detrimental involvement of NOS in stress hormone signalling, and the potential future benefits of NOS inhibition in highly stressed patients. Highlights: Cortisol increases production of reactive nitrogen species an induces DNA damage through a nitric oxide synthase mediated mechanism in breast cancer cells. Psychological stress promotes metastatic spread, and this in reversed by inhibition of NOS in vivo. Stress induces expression of genes associated with tumourigenesis in the lungs of tumour bearing-mice. Cortisol promotes the release of pro-tumourigenic monocyte chemoattractants.