PO-444 The emerging role of junctional adhesion molecule-A (JAM-A) as a novel drug target in ductal carcinoma in situ (DCIS)

Introduction Junctional Adhesion Molecule-A (JAM-A) is a cell-cell adhesion protein whose increased expression is associated with poor prognosis in patients with invasive breast cancer. However little is known about its potential role in early breast cancer, specifically ductal carcinoma in situ (DCIS). We investigated whether JAM-A is overexpressed in DCIS patient tissues, and whether its pharmacological antagonism using a novel inhibitor of JAM-A signalling, termed JBS-2, utilising in vitro and in vivo models of DCIS could reduce functional behaviours associated with tumorigenicity. Material and methods A patient tissue microarray (TMA) comprising DCIS samples (n=50) and normal adjacent tissue (NAT) (n =26) was stained for JAM-A and semi-quantitatively scored. Using a HER2/JAM-positive cell line model of DCIS, SUM-225 and an ex vivo primary DCIS breast culture, we investigated cell viability following pharmacological targeting of JAM-A and HER2/EGFR. The tolerability of JBS-2 in vivo was examined in NOD-SCID mice via intraperitoneal injection for 14 days. Finally, JBS-2 was tested for anti-tumorigenic effects alone or in combination with the HER2/EGFR tyrosine kinase inhibitor lapatinib in an in vivo mouse model of breast cancer following SUM-225 cell implantation in the mammary fat pad of NOD-SCID mice. Results and discussions Immunohistochemical analysis revealed 96% of DCIS tissues had moderate/high JAM-A expression in comparison to 23% of NAT. Treatment of SUM-225 cells with JBS-2 or lapatinib significantly inhibited cell viability in a concentration-dependent manner. Co-treatment of SUM-225 cells with JBS-2 and lapatinib additively inhibited cell viability over either treatment alone. JBS-2 also reduced cell viability on an ex vivo DCIS primary culture. NOD-SCID mice treated with JBS-2 for 14 days revealed no haematological, biochemical or histopathological toxicity. Importantly, in a SUM-225 orthotopic murine model of DCIS, treatment with JBS-2, either alone or in combination with lapatinib, significantly inhibited tumour progression. JAM-A staining of SUM-225 tumours following treatment revealed those treated with JBS-2 had a 30% reduction in JAM-A expression in comparison to the control. Conclusion The role of JAM-A in DCIS is unknown. Increased expression of JAM-A in DCIS tissues coupled with the responsiveness of a HER2-positive DCIS model to a JAM-A inhibitor suggests novel potential in investigating JAM-A inhibitors alone or in combination with HER2 inhibitors as preventative or therapeutic agents in this setting.