AbstractBreast 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
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.
|Date of Award
|Melanie Flint (Supervisor)