Expression of Retinoid Receptor Genes and Proteins in Non-Small-Cell Lung Cancer

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Abstract
BACKGROUND: Retinoids can suppress carcinogenesis in high-risk non-neoplastic bronchial lesions and can reduce the risk of second primary non-small-cell lung cancer (NSCLC). The effects of retinoids are mediated by nuclear receptors, i.e., the retinoic acid receptors (RARα, RARβ, and RARγ) and the retinoid X receptors (RXRα, RXRβ, and RXRγ). We investigated whether abnormalities in the in vivo expression of retinoid receptors are observed in NSCLC. METHODS: Expression of retinoid receptors in paired specimens of normal and cancerous tissues from the lungs of 76 patients with NSCLC was studied by use of anti-retinoid receptor antibodies (except those against RXRγ) and immunohistochemistry. RAR messenger RNAs were analyzed by use of in situ hybridization and by reverse transcription-polymerase chain reaction (RT-PCR). Samples were also studied for loss of heterozygosity (LOH) at chromosome 3p24. All P values are two-sided. RESULTS: All studied receptors were expressed in normal lung cells and in high- risk non-neoplastic lesions. In tumor cells, overexpression of RXRα and RARα was frequently observed. In contrast, RXRβ expression decreased in 18% of the tumor specimens. Furthermore, there was a marked decrease in the expression of RARβ in 63% of the tumors ( P <.0001). Decreased expression of RARγ was observed by RT-PCR in 41% of the tumors ( P <.0001). LOH at 3p24 was observed in 41% of the tumor specimens from informative patients and in 20% of the non-neoplastic lesions. CONCLUSIONS: Expression of RARα and RXRα is either normal or elevated in NSCLC. In contrast, a large percentage of tumors show a marked decrease in the expression of RARβ, RARγ, and RXRβ as well as a high frequency of LOH at 3p24, which was also observed in non-neoplastic lesions. These data suggest that altered retinoid receptor expression may play a role in lung carcinogenesis.