Suppression of retinoic acid receptor β 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 RARα, RARβ, RARγ, RXRα, RXRβ, and RXRγ 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. RARα, RXRα, and RXRγ were expressed in more than 95% of the NSCLC specimens. In contrast, RARβ, RARγ, and RXRβ expression was detected in only 42%, 72%, and 76% of NSCLC, respectively. Conclusions: These data suggest that the expression of RARα, RXRα, and RXRγ is not altered in NSCLC; however, expression of RARβ and possibly also of RARγ and RXRβ 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.