title: Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.
abstract: BACKGROUND
  Perp is a transcriptional target of both p53 during DNA damage-induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland.
  
  
  METHODS
  Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14-Cre/+;p53fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis.
  
  
  RESULTS
  We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer.
  
  
  CONCLUSIONS
  Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Center for Clinical Sciences Research Room 1255, 269 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Dusek
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Bascom
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baron
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003896:Desmosomes / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006706:Homeostasis; D053547:Keratin-14 / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D053547:Keratin-14; C507446:Krt14 protein, mouse; D008565:Membrane Proteins; C416404:PERP protein, human; C406964:Perp protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse