Nuclear retinoid acid receptor beta in bronchial epithelium of smokers before and during chemoprevention

Abstract

Background: Retinoids can reverse neoplastic lesions and prevent second primary tumors in the aerodigestive tract. These effects are thought to be mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each receptor group including three subtypes (α, β, and γ). Previously, we found that RARβ expression was suppressed in lung cancer. In this study, we investigated whether expression of RARβ is modulated by chemopreventive intervention. Methods: Using in situ hybridization, we analyzed RARβ messenger RNA (mRNA) expression in bronchial biopsy specimens from heavy smokers, at baseline and after 6 months of treatment with 13-cis- retinoic acid (13-cis-RA) or placebo. Since we had previously detected RARβ expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARβ mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant. Results: RARβ mRNA expression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group and in 24 (72.7%) of 33 subjects in the placebo group. After 6 months of 13-cis-RA treatment, the number of subjects who were RARβ positive in all six biopsy specimens increased from five of 35 to 13 of 35 (2.6-fold), so that the percentage of individuals with aberrant RARβ expression decreased to 62.9% (22 of 35), which represents a statistically significant difference from baseline expression (two-sided P = .01). In the placebo group, no statistically significant difference in RARβ expression was observed between baseline and 6 months. RARβ expression was not related to current smoking status or reversal of squamous metaplasia. Conclusions: These results indicate that RARβ is an independent marker of response to 13-cis-RA and may serve as an intermediate biomarker in chemoprevention trials of upper aerodigestive tract cancers.