Expression of retinoid receptor genes and proteins in non-small-cell lung cancer

Background: Retinoids can suppress carcinogenesis in high-risk nonneoplastic 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 (RAR alpha, RAR beta, and RAR gamma) and the retinoid X receptors (RXR alpha, RXR beta, and RXR gamma), 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 RXR gamma) and immunohistochemistry. RAR messenger RNAs were analyzed by use of irt 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 RXR alpha and RAR alpha was frequently observed. In contrast, RXR beta expression decreased in 18% of the tumor specimens. Furthermore, there was a marked decrease in the expression of RAR beta in 63% of the tumors (P<.0001). Decreased expression of RAR gamma 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 RAR alpha and RXR alpha is either normal or elevated in NSCLC, In contrast, a large percentage of tumors show a marked decrease in the expression of RAR beta, RAR gamma, and RXR beta 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.