Emily Rutherford June'20.pdf (12.67 MB)
Novel Clinical Roles for Junctional Adhesion Molecule-A in Breast Cancer Progression and Targeted Therapy-Associated Morbidities
thesisposted on 2021-12-14, 11:53 authored by Emily Rutherford
Although considerable progress has been made in breast cancer diagnosis and management, it remains a leading cause of morbidity and mortality. Furthermore, drug resistance and treatment-related adverse events are ongoing clinical issues. This thesis explores emerging roles for an adhesion protein, Junctional Adhesion Molecule-A (JAM-A) in breast cancer pathogenesis, the monitoring of response to treatment, and in treatment-associated morbidities.
Methods and Results: JAM-A can exist in either its nativemembrane-tethered configuration, or as an extracellularly-cleaved soluble protein termed cleaved JAM-A (cJAM-A). A combination of epidemiological and basic scientific investigations were employed to elucidate a role for different forms of JAM-A in breast cancer.
Epidemiological studies: This thesis revealed that high blood levels of cJAM-A correlated significantly with adverse outcomes in two independent cohorts of breast cancer patients. Despite known roles for cJAM-A in vascular function, adverse clinical events such as cardiotoxicity and thrombosis were infrequent in our cohorts and thus did not yield any correlation with cJAM-A levels. However, in relation to cardiotoxicity monitoring, deficits in knowledge and areas for clinical education in a group of trainee clinicians were identified.
Laboratory studies: Given the association between cJAM-A levels and poor patient outcomes, we tested if cJAM-A acted as a ligand driving pro-tumourigenic events. Recombinant cJAM-A (rcJAM-A) was rapidly internalised into breast cancer cells independently of macro- and micro-pinocytosis; furthermore, rcJAM-A stimulated breast cancer cellular proliferation in vitro. In a semi-in vivo chick embryo xenograft model, rcJAM-A significantly increased tumour size, and inhibition of JAM-A cleavage tended to reduce the formation of grossly visible xenograft tumours. Together with the fact that overexpression of membranous JAM-A was sufficient to increase the size of xenograft tumours; our results are consistent with novel potential roles for both forms of JAM-A in breast cancer.
Conclusion: Overall, the findings from this thesis in models spanning in vitro and semi-in vivo settings with translation into patient-centred contexts suggest that JAM-A holds promise as both a biomarker of breast cancer progression and a potential pharmacological target worthy of future research.
First SupervisorDr Ann Hopkins
Second SupervisorProf. Arnold Hill,
CommentsSubmitted for the Award of Doctor of Medicine to the Royal College of Surgeons in Ireland, 2020
Published CitationRutherford E,. Novel Clinical Roles for Junctional Adhesion Molecule-A in Breast Cancer Progression and Targeted Therapy-Associated Morbidities [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020
- Doctor of Medicine (MD)
Date of award2020-05-31
- Doctor of Medicine (MD)