Accumulation of p53 protein and retinoic acid receptor beta in retinoid chemoprevention.
Although retinoids have proven to be effective as chemopreventive agents in reversing premalignant oral lesions and preventing second primary tumors, their mechanisms of chemopreventive efficacy in clinical settings have not been established. To better define this mechanism, we studied p53 protein and retinoic acid receptor beta (RAR-beta) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-beta expression in 38 matched samples before and after treating them with isotretinoin. The study results were then compared with clinical responses. To detect p53 protein expression, 4-micrometer sections of formalin-fixed, paraffin-embedded tissue specimens were used for immunohistochemical analysis with a monoclonal anti-p53 antibody, and levels of p53 expression were recorded with a labeling index (LI). Expression of RAR-beta mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-beta mRNA was semiquantitated using scores from 0 (no expression) to 3+ (highest expression). p53 protein was detected in 85% of all lesions. High p53 protein expression (LI >/= 0.2) was detected in 25% of the lesions at baseline and in 18% of the lesions after isotretinoin therapy. The clinical response was 65% for lesions having low p53 expression (LI < 0.2) and 27% for lesions having high p53 expression (P = 0.027). Expression of RAR-beta mRNA was detected in 40% of the patients at baseline and increased to 90% of the patients after isotretinoin therapy (P < 0. 001). Seventy-two percent of the patients having low p53 expression had no RAR-betamRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-beta expression, which suggests that patients having low p53 expression tended to lose RAR-beta mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-beta mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-beta modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-beta after isotretinoin therapy achieved a 70% rate of major response. The patients with low p53 protein expression and either no change or down-regulation of RAR-beta or with high p53 expression and up-regulation of RAR-beta had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-beta had a response rate of only 14% to isotretinoin therapy. The basic mechanisms underlying the association between clinical responses and these two biomarkers need to be explored.
Shin
D M
DM
Departments of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, Texas 770.
Xu
X C
XC
Lippman
S M
SM
Lee
J J
JJ
Lee
J S
JS
Batsakis
J G
JG
Ro
J Y
JY
Martin
J W
JW
Hittelman
W N
WN
Lotan
R
R
Hong
W K
WK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D018890:Chemoprevention; D005260:Female; D006801:Humans; D006965:Hyperplasia; D017403:In Situ Hybridization; D015474:Isotretinoin / Q000627:therapeutic use*; D007971:Leukoplakia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D016588:Anticarcinogenic Agents; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D016159:Tumor Suppressor Protein p53; C082925:retinoic acid receptor beta; D015474:Isotretinoin