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 normal growth and differentiation of human bronchial epithelium. They are also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). These effects are thought to result from modulation of cell growth, differentiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] and 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 there are abnormalities in the expression of retinoid receptors in surgical specimens from patients with NSCLC. Methods: Transcripts of nuclear retinoid receptors were detected in formalin-fixed, paraffin-embedded 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 northern blotting, and the specificity of the binding of antisense riboprobes was verified by use of sense probes as controls. Results: All receptors were expressed in at least 89% of control normal bronchial tissue specimens from 17 patients, without a primary lung cancer and in distant normal bronchus specimens from patients with NSCLC. RAR alpha, RXR alpha, and RXR gamma were expressed in more than 95% of the NSCLC specimens. In contrast, RAR beta, RAR gamma, and RXR beta expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. Conclusions: These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta and possibly also of RAR gamma and RXR beta is suppressed in a large percentage of patients with lung cancer. Implications: The loss of expression of one or more of these nuclear retinoid receptors may be associated with lung carcinogenesis.