title: Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation.
abstract: Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12-dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn-sufficient wild-type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit-deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit(-/-) (Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild-type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2-fold in Fhit(-/-) versus wild-type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit(-/-) mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild-type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn-supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high-risk human cohorts.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pathology, College of Medicine, Columbus, Ohio.
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.|Biomedical Sciences Graduate Program, Columbus, Ohio.
authors.forename: Morgan S
authors.initials: MS
authors.lastname: Schrock
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: James
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xueliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Donald
authors.initials: D
authors.lastname: Quimby
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.affiliation: Department of Pathology, Anatomy & Cell Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Fong
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology*; D004249:DNA Damage; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D012867:Skin / Q000187:drug effects* / Q000473:pathology*; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology*; D047368:Tumor Burden; D015032:Zinc / Q000494:pharmacology*; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D015032:Zinc; D000099170:Bis(5'-adenosyl)triphosphatase
keywords: DMBA-induced skin tumors; Fhit knockout mice; tumor prevention; tumor suppressor-deficient mice; zinc supplementation