Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas

Yan Ma, Steven Fiering, Candice Black, Xi Liu, Ziqiang Yuan, Vincent A. Memoli, David J. Robbins, Heather A. Bentley, Gregory J. Tsongalis, Eugene Demidenko, Sarah J. Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Cyclin E is a critical G1-S cell cycle regulator aberrantly expressed in bronchial premalignancy and lung cancer. Cyclin E expression negatively affects lung cancer prognosis. Its role in lung carcinogenesis was explored. Retroviral cyclin E transduction promoted pulmonary epithelial cell growth, and small interfering RNA targeting of cyclin E repressed this growth. Murine transgenic lines were engineered to mimic aberrant cyclin E expression in the lung. Wild-type and proteasome degradation-resistant human cyclin E transgenic lines were independently driven by the human surfactant C (SP-C) promoter. Chromosome instability (CIN), pulmonary dysplasia, sonic hedgehog (Shh) pathway activation, adenocarcinomas, and metastases occurred. Notably, high expression of degradation-resistant cyclin E frequently caused dysplasia and multiple lung adenocarcinomas. Thus, recapitulation of aberrant cyclin E expression as seen in human premalignant and malignant lung lesions reproduces in the mouse frequent features of lung carcinogenesis, including CIN, Shh pathway activation, dysplasia, single or multiple lung cancers, or presence of metastases. This article reports unique mouse lung cancer models that replicate many carcinogenic changes found in patients. These models provide insights into the carcinogenesis process and implicate cyclin E as a therapeutic target in the lung.

Original languageEnglish (US)
Pages (from-to)4089-4094
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number10
DOIs
StatePublished - Mar 6 2007
Externally publishedYes

Keywords

  • Lung cancer
  • Lung carcinogenesis
  • Sonic hedgehog

ASJC Scopus subject areas

  • Genetics
  • General

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  • Cite this

    Ma, Y., Fiering, S., Black, C., Liu, X., Yuan, Z., Memoli, V. A., Robbins, D. J., Bentley, H. A., Tsongalis, G. J., Demidenko, E., Freemantle, S. J., & Dmitrovsky, E. (2007). Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas. Proceedings of the National Academy of Sciences of the United States of America, 104(10), 4089-4094. https://doi.org/10.1073/pnas.0606537104