Cell-cell junctions are critical for cell adhesion during normal epithelial homeostasis. The cardinal feature of the adherens junctions is the interaction between the cytoplasmic tail of classical type I (E-cadherin) and type II cadherins, and p120-catenin (p120ctn, also referred to as catenin, delta1 or Ctnnd1), which engenders stability of this specific junctions complex at the cell membrane (Davis et al., 2003
; Ireton et al., 2002
; Xiao et al., 2003
). Recently, it was revealed by X-ray crystallography that p120 isoform 4A is in complex with the juxtamembrane domain core region (JMD(core)) of E-cadherin (Ishiyama et al., 2010
). Loss of p120ctn or its phosphorylation on serine-threonine residues is able to destabilize E-cadherin (Fukumoto et al., 2008
). Thus, p120ctn regulates cadherin stability and turnover. The balance between adhesion and migration is regulated further by p120ctn’s ability to regulate the activities of RhoA, Rac and Cdc42 through the amino-terminus of p120ctn, thereby orchestrating exquisite actin dynamics (Reynolds and Roczniak-Ferguson, 2004
). Furthermore, the bridge between p120ctn and these effectors of migration involves p190RhoGAP (Wildenberg et al., 2006
p120ctn’s structure is highlighted by an amino-terminal domain has regulatory functions, a central Armadillo Repeat domain (Arm), a nuclear export signal (NES), and a carboxyl-terminal domain whose function(s) remain to be elucidated (Anastasiadis et al., 2000
). Isoforms of p120ctn result from differential splicing. Initiation at the first ATG start site (Isoform 1) results in preferential expression in the mesenchymal compartment, while isoforms that lack a coiled-coiled domain that utilize the third start site (Isoform 3) are expressed in the epithelial compartment. Not all isoforms express the NES.
It has become increasingly clear that loss, downregulation or mislocalization of p120ctn helps to define diverse tumor types in the prostate, breast, pancreas, colon, skin, bladder and endometrium (Reynolds and Roczniak-Ferguson, 2004
; Thoreson and Reynolds, 2002
; van Hengel and van Roy, 2007
). Interestingly, decreased expression is not typically observed in the entire tumor but rather in regions of the tumor, similar to that observed for E-cadherin loss (Birchmeier, 1995
). This loss or mislocalization of p120ctn frequently leads to E-cadherin destabilization, endowing a cancer cell an advantage in cell migration by virtue of abrogation of cell adhesion. Additionally, knockdown experiments using shRNA to p120ctn have demonstrated that p120ctn loss induces invasion in tumor cell lines with concomitant loss or down-regulation of E-cadherin (Macpherson et al., 2007
), although collective invasion might involve also concurrent retention of membranous p120ctn and cadherin mediated (P- or E-cadherin) cell-cell contacts at least in vitro
. In aggregate, these data suggest a potential tumor suppressor role for p120ctn in various cancer types, but a causal role in vivo
has yet to be demonstrated unequivocally.
P120ctn loss in the mouse has been modeled in an attempt to phenocopy human disease, but to date, no published mouse model has yielded a cancer phenotype. Deletion of p120ctn
by homologous recombination in mice results in embryonic lethality. Tissue-specific targeting of p120ctn
has been utilized to study the role of p120ctn
in development and tumorigenesis (Davis and Reynolds, 2006
). For example, p120ctn loss results in impaired enamel development (Bartlett et al., 2010
). Targeted p120ctn
deletion in the embryonic salivary gland forces a loss of acinar development and an adoption of a ductal cell fate. Although these mice die immediately in the postnatal period, the salivary glands are distinguished by intraepithelial dysplasia but not cancer (Davis and Reynolds, 2006
). P120ctn loss in the skin results in epidermal hyperplasia and chronic inflammation with loss of hair and body fat (Perez-Moreno et al., 2006
). Furthermore, the epidermis has evidence of NFκB activation and mitotic defects such as aneuploidy but no overt cancer (Perez-Moreno et al., 2008
). Recently, conditional p120ctn loss in the small intestine and colon was found to result in death by 21 days with evidence of mucosal erosion and bleeding, and recruitment of COX-2 expressing neutrophils, suggesting an underlying barrier defect (Smalley-Freed et al., 2010
). Thus, to date, no tissue specific p120ctn knockout mouse models have been able to demonstrate that p120ctn loss results in the development of invasive cancer.
The overarching goal of this study was to generate and characterize mechanistically a genetic mouse model in which conditional p120ctn loss in the squamous oral cavity, esophagus and forestomach results in cancer that phenocopies precisely the histologic features of human oral and esophageal squamous cell carcinomas (OSCC, ESCC, respectively). In so doing, such a model might provide a platform for the consideration of combinatorial therapeutics in ESCC, OSCC and potentially other squamous cell cancers.