**3.3 JAM proteins and the regulation of stromal cells**

The final grouping of breast cancer microenvironmental cells which will be discussed are stromal cells, broadly including fibroblasts and myoepithelial cells. Although little is known about JAM-mediated control of breast stromal cells specifically, insights from other cellular systems may suggest that this multifunctional family of proteins could have a hand in influencing the mesenchymal element of tumourigenic processes.

JAM-C expression has been noted on the surface of primary fibroblasts derived from human lung, skin and cornea (Morris *et al*., 2006). The same authors observed JAM-A and JAM-C expression on the widely-studied NIH-3T3 fibroblast cell line. Interestingly, high JAM-C expression on synovial fibroblasts has been associated with the pathology of murine experimental arthritis, and JAM-C antagonism shown to have functional benefits in reducing the severity of inflammation (Palmer *et al*., 2007). An immunohistochemical study in human arthritis has also demonstrated JAM-C expression on the synovial fibroblasts of both osteoarthritis and rheumatoid arthritis patients, in conjunction with JAM-C-dependent adhesion of myeloid cells to these fibroblasts (Rabquer *et al*., 2008). Enhanced expression of JAM-A has also been described on the skin of patients with the inflammatory disorder systemic sclerosis, in comparison to that on normal dermal fibroblasts (Hou *et al*., 2009).

Aside from facilitating adhesion of leukocytic cells to stromal elements such as fibroblasts, another way in which JAM family members could influence the breast cancer microenvironment is by altering proliferation of fibroblasts or other accessory cells. JAM-A has been reported to be required for proliferation of vascular smooth muscle cells, since JAM-A gene silencing exerted anti-proliferative effects in this system (Azari *et al*., 2010). Whether this is through direct or indirect mechanisms remains uncertain, particularly in light of conflicting evidence in intestinal epithelial cells suggesting that JAM-A expression restricts proliferation by inhibiting Akt-dependent Wnt signalling (Nava *et al*., 2011). However functional inhibition of the extracellular domain of JAM-A has been shown to inhibit bFGF-induced endothelial cell proliferation, and overexpression of JAM-A was also found to increase endothelial cell proliferation (Naik *et al*., 2003). Accordingly, very recent evidence has suggested that JAM-A expression exerts a negative tone on apoptosis in the mammary epithelium (Murakami *et al*., 2011). It is likely that processes as crucial as proliferation are strictly regulated in a spatial manner, which could account for tissuespecific differences as observed from the little available evidence to date. Whether or not JAM family members may influence proliferation of breast stromal cells like fibroblasts and the myoepithelium remains to be investigated. However, it is tempting to speculate that the acquisition of a proliferative phenotype in tumours may be co-ordinately linked to the promigratory "mesenchymal" phenotypes observed in many aggressive, poorly-differentiated breast cancers, to which evidence has already linked members of the JAM family. Co-culture models which better recapitulate the complexity of the breast cancer microenvironment than mono-cultures (Holliday *et al*., 2009) may offer promise in dissecting the relative cellular contributions of JAMs to tumour progression at a reductionist level.
