Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation.
OBJECTIVE
To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention.


METHODS
Data published until June 2006 are summarized, and previously unpublished results from our own research are included.


RESULTS
In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia.


CONCLUSIONS
Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.
Gautschi
Oliver
O
University of California Davis Cancer Center, Sacramento 95817, USA, and Clinic of Medical Oncology, University Hospital Bern, Bern, Switzerland. oliver.gautschi@ucdmc.ucdavis.edu
Ratschiller
Daniel
D
Gugger
Mathias
M
Betticher
Daniel C
DC
Heighway
Jim
J
D000236:Adenoma / Q000473:pathology / Q000503:physiopathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology* / Q000503:physiopathology*; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D011110:Polymorphism, Genetic
D019938:Cyclin D1