title: Role of PTEN in basal cell derived lung carcinogenesis.
abstract: Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor β receptor type II (TGFβRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Malkoski
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cleaver
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Thompson
authors.forename: Whitney P
authors.initials: WP
authors.lastname: Sutton
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Haeger
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Rodriguez
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.forename: Daniel
authors.initials: D
authors.lastname: Merrick
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism
chemical_list: D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; adenocarcinoma; non-small cell lung cancer; squamous cell carcinoma