Transgenic cyclin E triggers dysplasia and multiple pulmonary adenocarcinomas.
Cyclin E is a critical G(1)-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.
Ma
Yan
Y
Department of Pharmacology and Toxicology, and Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, NH 03755, USA.
Fiering
Steven
S
Black
Candice
C
Liu
Xi
X
Yuan
Ziqiang
Z
Memoli
Vincent A
VA
Robbins
David J
DJ
Bentley
Heather A
HA
Tsongalis
Gregory J
GJ
Demidenko
Eugene
E
Freemantle
Sarah J
SJ
Dmitrovsky
Ethan
E
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000378:metabolism; D019076:Transgenes
D019927:Cyclin E; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering