In this study, we found that mice with Pten knock out in Lgr5+ HFSCs showed increased incidences of skin papilloma and SCC upon DMBA/TPA induction, while double loss of Pten /CTNNB1(β‐catenin gene) or Pten/TNF in Lgr5+ HFSCs greatly diminished the tumorigenesis. Here, LGR5 is linked to skin papilloma.