Reiman et al. (2012) used microarray analysis to screen for targets of FLCN and found a preponderance of differentially expressed Wnt and Cadherin signalling genes in FLCN-null FTC-133 cells. The Cadherin pathway regulates cell-cell junction formation and has been recently linked to BHD as FLCN loss reduces the amount of E-cadherin at adherens junctions (Nahorski et al., 2012) and causes increased desmosome formation (Medvetz et al., 2012). Furthermore, E-cadherin expression was found to be mis-localised in BHD-associated kidney tumours (Kuroda et al., 2014) and FLCN-null murine alveolar epithelial type II cells (Goncharova et al., 2014), and cell-cell adhesion is increased in HBE cells (Khabibullin et al., 2014) suggesting that E-cadherin dysregulation might contribute to BHD pathogenesis in both kidney and lung tissues.

Loss of FLCN in mouse lung epithelial cells has also been shown to lead to the dysregulation of cell-cell contacts and formation of gaps between cells (Krymskaya et al., 2010). This was attributed to the mis-localisation of B-catenin (Krymskaya et al., 2010), a component of the Wnt signalling pathway, which transduces messages from the cell surface to the nucleus and has roles in embryonic development and tumorigenesis (Klaus and Birchmeier, 2008). More recently, FLCN has been shown to regulate planar cell polarity by sequestering B-catenin in cilia (Luijten et al., 2013).

Both pathways have been previously implicated in cancer, including renal cancer (Jeanes et al., 2008; Hsu et al., 2012) and these results suggest they may play a role in BHD-associated tumorigenesis.