Novel Clinical Roles for Junctional Adhesion Molecule-A in Breast Cancer Progression and Targeted Therapy-Associated Morbidities

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.