Nuclear Retinoid Acid Receptor Beta in Bronchial Epithelium of Smokers Before and During Chemoprevention

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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.