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 RARbeta expression was suppressed in lung cancer. In this study, we investigated whether expression of RARbeta is modulated by chemopreventive intervention.


METHODS
Using in situ hybridization, we analyzed RARbeta 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 RARbeta expression in 90% of bronchial specimens from nonsmokers, we considered loss of RARbeta mRNA expression in at least one of six biopsy specimens at baseline in this study to be aberrant.


RESULTS
RARbeta 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 RARbeta 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 RARbeta 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 RARbeta expression was observed between baseline and 6 months. RARbeta expression was not related to current smoking status or reversal of squamous metaplasia.


CONCLUSIONS
These results indicate that RARbeta 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.
Xu
X C
XC
Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Lee
J S
JS
Lee
J J
JJ
Morice
R C
RC
Liu
X
X
Lippman
S M
SM
Hong
W K
WK
Lotan
R
R
D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015415:Biomarkers; D001706:Biopsy; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004067:Digestive System Neoplasms / Q000209:etiology / Q000517:prevention & control*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D015474:Isotretinoin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000235:genetics; D012142:Respiratory Tract Neoplasms / Q000209:etiology / Q000517:prevention & control*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D015474:Isotretinoin