title: Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice.
abstract: Ptch1 is a key regulator of embryonic development, acting through the sonic hedgehog (SHH) signaling pathway. Ptch1 is best known as a tumor suppressor, as germline or somatic mutations in Ptch1 lead to the formation of skin basal cell carcinomas. Here we show that Ptch1 also acts as a lineage-dependent oncogene, as overexpression of Ptch1 in adult skin in K14Ptch(FVB) transgenic mice synergizes with chemically induced Hras mutations to promote squamous carcinoma development. These effects were not because of aberrant activation of SHH signaling by the K14Ptch(FVB) transgene, as developmental defects in the highest expressing transgenic lines were consistent with the inhibition of this pathway. Carcinomas from K14Ptch(FVB) transgenic mice had only a small number of nonproliferative Ptch1 transgene-positive cells, suggesting that the Ptch1 transgene is not required for tumor maintenance, but may have a critical role in cell-fate determination at the initiation stage.
authors.affiliation: Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94158, USA.
authors.forename: Hio Chung
authors.initials: HC
authors.lastname: Kang
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
authors.forename: Reyno
authors.initials: R
authors.lastname: Del Rosario
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D047109:Fetal Development / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D019076:Transgenes
chemical_list: D053823:Hedgehog Proteins; D053547:Keratin-14; C507446:Krt14 protein, mouse; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)