title: mTOR inhibition prevents rapid-onset of carcinogen-induced malignancies in a novel inducible HPV-16 E6/E7 mouse model.
abstract: The rising incidence of human papillomavirus (HPV)-associated malignancies, especially for oropharyngeal cancers, has highlighted the urgent need to understand how the interplay between high-risk HPV oncogenes and carcinogenic exposure results in squamous cell carcinoma (SCC) development. Here, we describe an inducible mouse model expressing high risk HPV-16 E6/E7 oncoproteins in adults, bypassing the impact of these viral genes during development. HPV-16 E6/E7 genes were targeted to the basal squamous epithelia in transgenic mice using a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA) system. After doxycycline induction, both E6 and E7 were highly expressed, resulting in rapid epidermal hyperplasia with a remarkable expansion of the proliferative cell compartment to the suprabasal layers. Surprisingly, in spite of the massive growth of epithelial cells and their stem cell progenitors, HPV-E6/E7 expression was not sufficient to trigger mTOR activation, a key oncogenic driver in HPV-associated malignancies, and malignant progression to SCC. However, these mice develop SCC rapidly after a single exposure to a skin carcinogen, DMBA, which was increased by the prolonged exposure to a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thus, only few oncogenic hits may be sufficient to induce cancer in E6/E7 expressing cells. All HPV-E6/E7 expressing SCC lesions exhibited increased mTOR activation. Remarkably, rapamycin, an mTOR inhibitor, abolished tumor development when administered to HPV-E6/E7 mice prior to DMBA exposure. Our findings revealed that mTOR inhibition protects HPV-E6/E7 expressing tissues form SCC development upon carcinogen exposure, thus supporting the potential clinical use of mTOR inhibitors as a molecular targeted approach for prevention of HPV-associated malignancies.
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Callejas-Valera
authors.affiliation: Developmental Skin Biology Section (HNB-254), NIH/NIAMS Building 50., Bethesda, MD 20814-4340, USA.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Iglesias-Bartolome
authors.forename: Panomwat
authors.initials: P
authors.lastname: Amornphimoltham
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, 28049 Spain and.
authors.forename: Julia
authors.initials: J
authors.lastname: Palacios-Garcia
authors.affiliation: Oral and Pharyngeal Cancer Branch, NIH/NIDCR, Building 30, Bethesda, MD 20892-2190, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000235:genetics; D009959:Oropharyngeal Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D010703:Phorbol Esters / Q000633:toxicity; D012097:Repressor Proteins / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002273:Carcinogens; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D010703:Phorbol Esters; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D015127:9,10-Dimethyl-1,2-benzanthracene; C000600213:12-O-undecadienoylphorbol-13-acetate; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus