The importance of disrupted cell-cell adhesion for cancer development is underscored by the observed downregulation of adherens junction components during human cancer progression and genetic experiments demonstrating tumor prone phenotypes of mice deficient for E-cadherin, Alpha-catenin, or p120-catenin, components of the adherens junction 
. In contrast, the data regarding desmosome protein expression during human cancer progression are conflicting 
, and the contribution of desmosome dysfunction to cancer development has not been clearly established using in vivo
mouse models. Here, we show that loss of the desmosomal component Perp predisposes mice to UVB-induced SCC development by enhancing both tumor initiation and progression. The effects of Perp
ablation are at multiple levels, leading both to compromised apoptosis in response to ultraviolet light and loss of desmosomal adhesion (). The defective apoptosis could allow the inappropriate survival of damaged cells, which could help initiate tumors. The exact mechanism through which Perp promotes apoptosis remains to be elucidated, but it may relate to Perp function at the desmosome, as apoptotic defects were previously reported in cells lacking either the desmosomal component desmoglein 1 or desmoglein 2 
. In addition, compromised UVB-induced apoptosis in the epidermis has also been observed in mice lacking the p53 target gene Noxa
, a member of the Bcl-2 family 
. Our findings indicate that Noxa is insufficient to drive apoptosis in the absence of Perp, and therefore that Perp and Noxa may collaborate to cause apoptosis. In addition, we observe perturbations in desmosomal adhesion. Interestingly, the desmosome downregulation we observe in tumors occurs without adherens junction loss or other signs of EMT, highlighting a specific role for desmosome loss in tumor development. It may be that desmosome loss occurs during early stages of tumorigenesis, facilitating early cancer progression, and that adherens junctions are lost subsequently, thereby promoting invasion and metastasis phenotypes. Our analysis of human SCC samples supports the idea that PERP-deficient, E-cadherin positive samples reflect an important stage of human skin carcinogenesis.
Model for how Perp-deficiency can promote tumorigenesis.
To understand further how Perp
-deficiency might enhance tumor development, we examined gene expression profiles upon Perp
loss. Interestingly, several of the genes induced upon Perp
inactivation are known to be involved in promoting inflammation and tumorigenesis 
. Inflammation is a well-established causative factor in tumorigenesis 
, as evidenced by tumor-prone mouse strains deficient for specific subsets of immune or inflammatory cells exhibiting reduced tumor burdens 
. The induction of a set of inflammation-associated genes presents a plausible explanation for how Perp
-deficiency can promote cancer in cooperation with chronic UVB damage. Indeed, we found that Perp-deficiency, in conjunction with chronic UVB exposure, led to the infiltration of T-cells and mast cells. Mast cells can clearly promote tumorigenesis 
, and their accumulation in the UVB-treated, Perp-deficient epidermis provides another mechanism through which Perp loss can stimulate cancer development ().
Some of the previous controversy about whether desmosomal components promote or inhibit cancer may relate to differences in the contribution of desmosomes in different contexts. Depending on the tissue type, the genetic lesions already accrued, and the tissue microenvironment, desmosome-deficiency may have different effects. Indeed, certain proteins, such as Tgf-ß1 and E2f1, can have either pro- or anti-tumorigenic roles depending on the exact setting 
. Consistent with this notion, skin carcinogenesis experiments in which Perp
-deficient mice were treated with DMBA/TPA showed that Perp
loss actually hindered the development of papillomas, suggesting that Perp enables the formation of this type of tumor 
. Importantly, however, loss of the p53 tumor suppressor in this model also reduces papilloma formation, suggesting that this may represent an atypical route to tumorigenesis 
. Therefore, in the study described here, we sought to analyze Perp function in an accurate model for human cancer, by treating mice with UVB, the causative factor for SCC of the skin.
Our studies also provide insight into mechanisms of p53-mediated tumor suppression in skin cancer. The relevance of p53 in skin cancer development is highlighted by the observations that p53
is mutated in at least 90% of human SCCs 
and that p53
null mice display an enhanced predisposition to UVB-triggered skin cancer 
. While p53's ability to drive apoptosis in response to ultraviolet light has been shown to limit SCC formation 
, the molecular pathways underlying p53's tumor suppressor properties are incompletely understood. p53 is a transcriptional activator, but the genes mediating p53 tumor suppressor function have been unclear, as none of the mouse strains deficient for p53 target genes exhibits a spontaneous tumor predisposition 
. Instead, analysis of target genes in specific contexts may reveal key functions as mediators of p53 tumor suppressor function. This notion is exemplified by studies of the apoptotic target gene Puma
, which is important for p53 tumor suppression in the setting of Eμ-myc driven B-cell lymphomas 
. Our studies have provided important novel insight into pathways of p53 tumor suppression by suggesting that Perp is a critical mediator of p53 tumor suppressor function in UVB-induced SCC development. In addition, although the role of p63 in cancer has been more controversial, Perp loss could also potentially explain how tumors might arise in the absence of p63.
Non-melanoma skin cancer is one of the most common malignancies in the US 
. Fortunately, identifying SCC lesions before they progress into poorly differentiated tumors is aided both by facile detection and increased awareness of the consequences of chronic sun exposure. However, this is not the case for other stratified epithelia-derived cancers such as head and neck or esophageal cancers, which have poor survival rates 
. Our findings may provide a framework to better understand how these more deadly diseases progress. Indeed, the loss of desmosomal component expression with maintenance of adherens junction expression observed in the K14CreER;Perpfl/fl
mouse tumors and in human skin SCCs was recapitulated in samples derived from humans with head and neck SCCs (data not shown). The idea that desmosome loss may precede adherens junction loss could have important clinical implications. While E-cadherin status can provide a useful prognostic indicator for a variety of epithelial cancers, loss of this marker is associated with late-stage tumor progression 
. Identifying markers like PERP that are altered earlier during tumorigenesis could potentially enhance diagnosis, grading, and prognostication, leading to more informed choices of therapy. The increased frequency of advanced tumors in the Perp-deficient mice relative to controls supports the idea that human tumors lacking PERP may ultimately progress more aggressively, and thus that PERP status may provide a useful diagnostic or prognostic marker. Indeed, previously published expression profiling studies suggest that PERP may be one in a group of key predictors for patient treatment response in esophageal cancers 
. Further investigation of the potential diagnostic and prognostic value of PERP expression in human cancers represents an exciting avenue to pursue.