The impact of stress hormones on brain metastasis in breast cancer

Abstract

Brain metastases represent one of the most devastating and clinically challenging outcomes of advanced breast cancer, particularly within triple-negative breast cancer (TNBC), where therapeutic options remain limited, and prognosis is poor. Increasing evidence indicates that psychological stress and its hormonal mediators, such as norepinephrine (NE) and cortisol, can accelerate metastatic progression, but the molecular mechanisms linking stress signalling to brain colonisation are not fully understood. The overall aim of this thesis was to elucidate how stress hormones influence breast-cancer brain metastasis and to identify key molecular mediators involved in this process. Based on its established roles in cell adhesion, extracellular-matrix (ECM) remodelling, and survival signalling, Transglutaminase-2(TG2) was investigated as a candidate effector linking stress responses to metastatic behaviour.
This work demonstrates for the first time that TG2 is a stress-responsive enzyme in breast cancer. Catecholaminergic stimulation with NE induced TG2 expression, while propranolol (PRO) attenuated this effect. Inhibition of TG2 consistently reduced cell migration without affecting proliferation, establishing TG2 as a mechanistic driver of metastatic motility and a potential therapeutic target.
Proteomic profiling revealed that both stress and TG2 inhibition remodelled the proteome, particularly pathways related to ECM organisation, cytoskeletal remodelling and vesicle trafficking. Several members of the matrix-metalloproteinase (MMP) family and the tumour-suppressor RB1 were represented within these TG2-associated networks, supporting their relevance to stress-linked metastatic processes. EV miRNA analysis further identified a TG2-dependent reduction in miR-1290, a microRNA previously implicated in astrocyte activation and brain metastatic niche formation. Together, these findings suggest that TG2 modulates EV cargo composition in ways that may influence the brain microenvironment.
To evaluate translational relevance, patient-derived breast-cancer explants (PDEs)were used as physiologically preserved models that retain epithelial-stromal architecture. Immunohistochemical analysis confirmed variable expression of RB1, identified in proteomic datasets, and MMP9, with higher levels observed in explants from deceased patients, consistent with their association with aggressive and stress linked phenotypes.
In summary, this thesis demonstrates that stress hormones promote pro-metastatic signalling through TG2, which integrates catecholaminergic activation, ECM remodelling and EV-mediated communication to support brain metastasis in breast cancer. These findings provide mechanistic and translational insight into the stress–TG2–EV axis, identifying it as a potential therapeutic target for limiting metastatic progression in aggressive disease.

Date of Award	Feb 2026
Original language	English
Awarding Institution	University of Brighton
Supervisor	Melanie Flint (Supervisor) & Nicolas Stewart (Supervisor)