title: ERBB2 Is Essential for the Growth of Chemically Induced Skin Tumors in Mice.
abstract: Although the epidermal growth factor receptor has established roles in skin carcinogenesis, inflammation, and wound healing, the functions of the structurally related receptor ERBB2 in this tissue remain poorly explored. To assess the functions of ERBB2 in skin homeostasis, tumorigenesis, and wound healing, we employed keratin 5-directed, cre recombinase-mediated targeting of Erbb2 alleles in mice. Erbb2delmice, lacking ERBB2 specifically in keratinocytes, showed no noticeable spontaneous skin abnormalities. During early wound healing, the thickness and the number and proliferation rate of keratinocytes in the wound epithelium of Erbb2delmice were significantly reduced. Compared with control littermates, Erbb2delmice remained free of papillomas for a longer time and had significantly reduced tumor burden after application of the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate multistage chemical carcinogenesis protocol. Furthermore, tumor cell proliferation was substantially reduced in Erbb2delmice, and loss of ERBB2 also decreased keratinocyte proliferation after 12-O-tetradecanoylphorbol-13-acetate application. Thus, ERBB2 is dispensable for the development and homeostasis of the epidermis and its appendages. However, reflecting its pro-proliferative role, ERBB2 is required for the normal healing of skin wounds and for the progression of tumors during skin chemical carcinogenesis in mice. Thus, ERBB2 may be a promising target for inhibiting human nonmelanoma skin cancer progression.
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Dahlhoff
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Sukalp
authors.initials: S
authors.lastname: Muzumdar
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany. Electronic address: marlon.schneider@lmu.de.
authors.forename: Marlon R
authors.initials: MR
authors.lastname: Schneider
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001707:Biopsy, Needle; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012016:Reference Values; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D018709:Statistics, Nonparametric
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse