title: Loss of endogenous Nfatc1 reduces the rate of DMBA/TPA-induced skin tumorigenesis.
abstract: Immunosuppressive therapies using calcineurin inhibitors, such as cyclosporine A, are associated with a higher incidence of squamous cell carcinoma formation in mice and humans. Calcineurin is believed to suppress tumorigenesis in part through Nfatc1, a transcription factor expressed primarily in hair follicle bulge stem cells in mice. However, mice overexpressing a constitutively active Nfatc1 isoform in the skin epithelium developed increased spontaneous skin squamous cell carcinomas. Because follicular stem cells can contribute to skin tumorigenesis, whether the endogenous expression of Nfatc1 inhibits or enhances skin tumorigenesis is unclear. Here we show that loss of the endogenous expression of Nfatc1 suppresses the rate of DMBA/TPA-induced skin tumorigenesis. Inducible deletion of Nfatc1 in follicular stem cells before tumor initiation significantly reduces the rate of tumorigenesis and the contribution of follicular stem cells to skin tumors. We find that skin tumors from mice lacking Nfatc1 display reduced Hras codon 61 mutations. Furthermore, Nfatc1 enhances the expression of genes involved in DMBA metabolism and increases DMBA-induced DNA damage in keratinocytes. Together these data implicate Nfatc1 in the regulation of skin stem cell-initiated tumorigenesis via the regulation of DMBA metabolism.
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Jill
authors: J
authors: Goldstein
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Eve
authors: E
authors: Roth
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Natalie
authors: N
authors: Roberts
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Rachel
authors: R
authors: Zwick
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Samantha
authors: S
authors: Lin
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Sean
authors: S
authors: Fletcher
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Ana
authors: A
authors: Tadeu
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520.
authors: Christine
authors: C
authors: Wu
authors: Department of Comparative Medicine, Yale University, New Haven, CT 06520.
authors: Amanda
authors: A
authors: Beck
authors: Department of Comparative Medicine, Yale University, New Haven, CT 06520.
authors: Caroline
authors: C
authors: Zeiss
authors: Departments of Population Health Science and Policy, Genetics and Genomics Science, and Dermatology, Icahn School of Medicine, New York, NY 10029.
authors: Mayte
authors: M
authors: Suárez-Fariñas
authors: Department of Molecular, Cell and Developmental Biology, Yale University, New Haven, CT 06520 Department of Dermatology, Yale University, New Haven, CT 06520 valerie.horsley@yale.edu.
authors: Valerie
authors: V
authors: Horsley
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000302:isolation & purification / Q000493:pharmacokinetics; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced* / Q000378:metabolism*; D002273:Carcinogens; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004249:DNA Damage; D018859:Hair Follicle / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D002273:Carcinogens; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D019392:Cytochrome P-450 CYP2E1; D013755:Tetradecanoylphorbol Acetate