Background: Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of ROS/RNS as well as interfering with DNA repair processes, promoting tumourigenesis. Methods: Breast cancer cell lines were incubated with physiological levels of cortisol and norepinephrine (NE) in the presence and absence of receptor antagonists and iNOS inhibitors and DNA damage measured using phosphorylated γ-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect reactive oxygen/nitrogen species (ROS/RNS) in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours of stressed versus control animals and expression of iNOS and GR-associated Src in response to cortisol were examined using western blotting and qRT-PCR. Results: Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Although acute exposure to cortisol did not increase iNOS expression, the production of RNS was attenuated in the presence of an iNOS blocker (1400W). Src dissociates from the glucocorticoid receptor complex after acute cortisol exposure and levels of cortisol induced RNS decrease in response to a Src blocker. Conclusion: These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner through the release of Src to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer.
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- Breast cancer
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- School of Applied Sciences - Prof. Clinical and Bioanalytical Chemistry
- Applied Chemical Sciences Research and Enterprise Group
- Medicines Optimisation Research and Enterprise Group
- Centre for Lifelong Health