1. ¹OHSU Cancer Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
2. ²Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
3. ³Veterans Administration Medical Center, 3710 Southwest United States Veteran's Hospital Road, Portland, OR 97239, USA
4. ⁴Department of Molecular and Medical Genetics, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
5. ⁵Department of Environmental and Biomolecular Systems, Oregon Graduate Institute, Oregon Health & Science University, 20000 Northwest Walker Road, Beaverton, OR 97006, USA

Correspondence: Dr LE Hays, Oregon Health & Science University, 3710 Southwest United States Veteran's Hospital Road, R&D-2, Portland, OR 97239, USA. E-mail: haysl@ohsu.edu

Received 28 September 2007; Revised 18 February 2008; Accepted 12 March 2008; Published online 13 May 2008.

Abstract

Chromosomal abnormalities are commonly found in bronchogenic carcinoma cells, but the molecular causes of chromosomal instability (CIN) and their relationship to cigarette smoke has not been defined. Because the Fanconi anaemia (FA)/BRCA pathway is essential for maintenance of chromosomal stability, we tested the hypothesis that cigarette smoke suppresses that activity of this pathway. Here, we show that cigarette smoke condensate (CSC) inhibited translation of FANCD2 mRNA (but not FANCC or FANCG) in normal airway epithelial cells and that this suppression of FANCD2 expression was sufficient to induce both genetic instability and programmed cell death in the exposed cell population. Cigarette smoke condensate also suppressed FANCD2 function and induced CIN in bronchogenic carcinoma cells, but these cells were resistant to CSC-induced apoptosis relative to normal airway epithelial cells. We, therefore, suggest that CSC exerts pressure on airway epithelial cells that results in selection and emergence of genetically unstable somatic mutant clones that may have lost the capacity to effectively execute an apoptotic programme. Carcinogen-mediated suppression of FANCD2 gene expression provides a plausible molecular mechanism for CIN in bronchogenic carcinogenesis.