Stress hormone signalling contributes to tumourigenesis through the production of ros/rns, induction of dna damage and interference with chemotherapy in breast cancer

  • RenĂ©e Lee Flaherty

    Student thesis: Doctoral Thesis


    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
    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 AwardOct 2017
    Original languageEnglish
    Awarding Institution
    • University of Brighton
    SupervisorMelanie Flint (Supervisor)

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