1. ¹Department of Pathology, Stanford University, Stanford, CA, USA
2. ²Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
3. ³Institute of Pathology, University Hospital Charité, Berlin, Germany
4. ⁴Department of Genetics, Stanford University, Stanford, CA, USA
5. ⁵Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
6. ⁶Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Correspondence: Dr JR Pollack, Department of Pathology, Stanford University School of Medicine, CCSR-3245A, 269 Campus Drive, Stanford, CA 94305-5176, USA. E-mail: pollack1@stanford.edu

Received 27 July 2007; Revised 24 October 2007; Accepted 1 December 2007; Published online 21 January 2008.

Abstract

Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (thyroid transcription factor 1; also called NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein levels. Small interfering RNA (siRNA)-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival and implicate TITF1 as a lineage-specific oncogene in lung cancer.