AbstractAlthough there have been major advances in cancer research, breast cancer remains the most common cancer in women in the UK and cancer metastasis is the most common reason for cancer-related deaths. From the time of diagnosis, patients with breast cancer experience elevated levels of psychological stress that exert its effect on the body via stress hormones. Pre-clinical evidence suggests that the stress hormone cortisol, by acting on the glucocorticoid receptor, promotes breast cancer progression. The immune system plays an important role in breast cancer. This research aims to explore the effect of cortisol, mediated by the glucocorticoid receptor, on breast cancer metastasis to the brain via investigating different cross talks such as the immune system, the brain physiology, and the role of cancer-induced exosomes.
To investigate the immune cancer interactions, a 3D co-culture model was created, which showed that cortisol decreases the immune infiltration into the tumour and decreases the immune infiltration marker CXCL10 in 4T1 and 66CL4 cell lines. Using the 4T1 syngeneic in vivo model in BALB/c mice, we showed that chronic psychological stress, increased the levels of corticosterone in the blood, increased metastasis, and increased the ratio of CD4/CD8 immune infiltration into the primary tumour. Selectively blocking the glucocorticoid receptor using antagonists CORT125134 and CORT113176 reversed the effects of stress and restored CXCL10. To investigate the brain physiology, the tumour bearing mice brains underwent Tandem mass tag (TMT) proteomic analysis which showed that psychological stress altered the proteomic profile by regulating tumour suppressor proteins and inducing pro tumour proteins. Interestingly, CORT113176 reversed these actions, and it caused some beneficial off-target effects on the brain proteomic profile. The cross-talk between exosomes induced by breast cancer cells and the immune system was also investigated, but failed to show any significant effects.
In summary, this study proposes that cortisol plays a role in increasing metastasis to the brain by affecting the anti-tumour immunity while also affecting the structural brain physiology, allowing for metastasis to occur. This research also suggests that using glucocorticoid receptor antagonism could negate the effects of cortisol and could represent a potential for an adjuvant therapy strategy for patients with triple negative breast cancer.
|Date of Award
|Melanie Flint (Supervisor) & Nicolas Stewart (Supervisor)