**4. JAMs as novel potential drug targets in breast cancer**

The pleiotrophic roles of JAM family members in regulating both the breast epithelium and cells of the microenvironment may suggest JAMs as novel therapeutic targets for the future management of breast cancer. Whether by aiming to block migratory behaviour, angiogenesis, proliferation or to promote polarisation and differentiation, selective pharmacological targeting of JAM molecules could prove particularly useful in cancers that overexpress one or more JAMs. This naturally pre-supposes that JAMs are causally involved in the disease process rather than simply acting as passive biomarkers, a fact that remains to be solidified. However, irrespective of the last caveat, another facet worth exploring is the potential of targeting JAMs to promote drug delivery. Since tight junctions (TJs) as a whole are primary regulators of paracellular transport across epithelial cells (Gonzalez-Mariscal *et al*., 2005), successful drug delivery may require modulation of TJ proteins to allow drug molecules to pass (Matsuhisa *et al*., 2009). However disruption of TJ proteins for drug delivery purposes is a double-edged sword, given the risk of disrupting homeostatic mechanisms of polarity, differentiation and migration which are tightly regulated by TJs in normal tissues and whose dysregulation may themselves promote tumourigenesis.

As yet, there are no cancer therapies on the market which specifically target tight junctions. However several tight junction proteins have been described as receptors for specific molecules or organisms, and as such, these might provide valid and novel targets for drug delivery. A particular precedent exists with the claudin family of TJ proteins; Claudins-3 and -4 having been suggested as drug delivery targets since they act as the receptor for *Clostridium perfringens* enterotoxin (CPE). The ability of CPE to rapidly and specifically lyse cells expressing claudin-3 or -4 could potentially be exploited in the treatment of breast cancers over-expressing these proteins (Katahira *et al*., 1997; Morin, 2005; Santin *et al*., 2007; Santin *et al*., 2007). Sub-lytic doses of CPE could alternatively be used to compromise TJs thus enhancing the influx of drug molecules across the epithelium. This could be of particular benefit in accessing hypoxic tumour cores, around which the tumour cells may be very tightly packed and thus relatively inaccessible to chemotherapeutic drugs. To date CPE administration has been shown to reduce growth of claudin-4 overexpressing pancreatic tumour cells (Michl *et al*., 2001; Michl *et al*., 2003), but their potential use in other cancer settings remains an open question.

How JAM molecules might be therapeutically targeted also remains an unanswered question, but one could predict value in using monoclonal antibodies or small molecule inhibitors to block the signalling functions which contribute to processes such as migration and angiogenesis. However, to date, the role of JAMs as chemotherapeutic targets (or even prognostic/predictive biomarkers) in the clinical setting of breast cancer has yet to be elucidated and validated. Following the lead of JAM-A as a potential biomarker and therapeutic target for breast cancer (McSherry *et al*., 2009; Gotte *et al.,* 2010; McSherry *et al.*, 2011; Murakami *et al.,* 2011), we speculate that this will be a lucrative area of research in the future.
