SUPPRESSION OF RETINOIC ACID RECEPTOR-BETA IN NON-SMALL-CELL LUNG-CANCER IN-VIVO - IMPLICATIONS FOR LUNG-CANCER DEVELOPMENT

Background: Retinoids, analogues of vitamin A, are required for the no rmal growth and differentiation of human bronchial epithelium. They ar e also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). Thes e effects are thought to result from modulation of cell growth, differ entiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] a nd retinoid X receptors [RXRs]), which mediate most retinoid actions, are suppressed, abnormal activity may result that could enhance cancer development. Purpose: This study was designed to determine whether th ere are abnormalities in the expression of retinoid receptors in surgi cal specimens from patients with NSCLC. Methods: Transcripts of nuclea r retinoid receptors were detected in formalin-fixed, paraffin-embedde d specimens by use of digoxigenin-labeled riboprobes specific for RAR alpha, RAR beta, RAR gamma, RXR alpha, RXR beta, and RXR gamma for in situ hybridization to histologic specimens from 79 patients with NSCLC and as control from 17 patients with non-lung cancer. The quality and specificity of the digoxigenin-labeled probes were determined by nort hern blotting, and the specificity of the binding of antisense ribopro bes was verified by use of sense probes as controls. Results: All rece ptors were expressed in at least 89% of control normal bronchial tissu e specimens from 17 patients, without a primary lung cancer and in dis tant normal bronchus specimens from patients with NSCLC. RAR alpha, RX R alpha, and RXR gamma were expressed in more than 95% of the NSCLC sp ecimens. In contrast, RAR beta, RAR gamma, and RXR beta expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. Conclusion s: These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta an d possibly also of RAR gamma and RXR beta is suppressed in a large per centage of patients with lung cancer. Implications: The loss of expres sion of one or more of these nuclear retinoid receptors may be associa ted with lung carcinogenesis.