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

Background: Retinoids can reverse neoplastic lesions and prevent second pri mary tumors in the aerodigestive tract. These effects are thought to be med iated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (R XRs), each receptor group including three subtypes (alpha, beta, and gamma) , Previously, we found that RAR beta expression was suppressed in lung canc er. In this study, we investigated whether expression of RAR beta is modula ted by chemopreventive intervention. Methods: Using in situ hybridization, we analyzed RAR beta messenger RNA (mRNA) expression in bronchial biopsy sp ecimens from heavy smokers, at baseline and after 6 months of treatment wit h 13-cis-retinoic acid (13-cisRA) or placebo. Since we had previously detec ted RAR beta expression in 90% of bronchial specimens from nonsmokers, we c onsidered loss of RAR beta mRNA expression in at least one of six biopsy sp ecimens at baseline in this study to be aberrant. Results: RAR beta mRNA ex pression was aberrant in 30 (85.7%) of 35 subjects in the 13-cis-RA group a nd 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 t hat the percentage of individuals with aberrant RAR beta expression decreas ed to 62.9% (22 of 35), which represents a statistically significant differ ence from baseline expression (two-sided P = .01). In the placebo group, no statistically significant difference in RAR beta expression was observed b etween baseline and 6 months, RAR beta expression was not related to curren t smoking status or reversal of squamous metaplasia. Conclusions: These res ults 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.