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Breast cancer affects 1 in 8 women in the UK, and breast cancer patients often report increased levels of psychological stress. Psychological stress results in an increase in the circulating levels of the stress hormones glucocorticoids and catecholamines. Currently, few molecular mechanisms exist linking the actions of stress hormones and breast cancer progression. However, it has recently been suggested that stress hormones can promote DNA damage through the generation of reactive oxygen/nitrogen species (ROS/RNS). This research aims to explore the effect of stress hormone signalling on breast cancer progression and response to treatment. The generation of ROS/RNS and induction of DNA damage was measured in breast cancer cell lines. Pharmacological inhibition of the glucocorticoid receptor (GR) and inducible nitric oxide synthase (iNOS) was used to negate the effects of stress hormone exposure. Psychological stress, using restraint stress, was induced in a syngeneic mouse model of breast cancer, alongside in vivo inhibition of NOS. DNA damage and repair process were examined in response to the glucocorticoid cortisol in an endocrine therapy resistant cell line, and the effect of exposure to the exogenous glucocorticoid dexamethasone on the efficacy of chemotherapy in breast cancer cells was also explored. Stress hormones were shown to induce the generation of ROS/RNS and promote DNA damage. Specifically, exposure to cortisol produced an increase in nitric oxide (NO) through an iNOSmediated pathway. Inhibition of both the GR and iNOS reduced cortisol-induced DNA damage. In a mouse model of breast cancer, inhibition of NOS significantly reduced primary tumour volume, angiogenic signalling in the primary tumour and metastatic spread in stressed mice. Cortisol increased ROS/RNS and DNA damage in endocrine therapy resistant breast cancer cells compared to parental cells, and deregulated DNA repair processes. The cytotoxic effect of chemotherapy agents was reduced in response to co-treatment with the glucocorticoid dexamethasone, through upregulation of the antioxidant response. In conclusion, this research demonstrates that stress hormones impact tumourigenic progression in breast cancer through the induction of DNA damage, mediated by the release of NO. This data also shows that endocrine resistant breast cancer cells are more responsive to the actions of glucocorticoids on DNA damage and repair. Furthermore, exogenous glucocorticoids can impair the efficacy of chemotherapies, through the generation of ROS/RNS. The role of psychological stress should therefore be considered in the treatment of breast cancer patients, and stress hormone receptor signalling could provide potential therapeutic targets for the treatment of breast cancers. |
