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

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 (alpha, beta, and gamma), Previously, we found that RAR beta expression was suppressed in lung cancer. In this study, we investigated whether expression of RAR beta is modulated by chemopreventive intervention. Methods: Using in situ hybridization, we analyzed RAR beta 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-cisRA) or placebo. Since we had previously detected RAR beta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RAR beta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant. Results: RAR beta 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 RAR beta 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 RAR beta 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 RAR beta expression was observed between baseline and 6 months, RAR beta expression was not related to current smoking status or reversal of squamous metaplasia. Conclusions: These results indicate that RAR beta 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.