Accumulation of p53 protein and retinoic acid receptor β in retinoid chemoprevention

Dong M. Shin, Xiao Chun Xu, Scott M. Lippman, J. Jack Lee, Jin S. Lee, John G. Batsakis, Jae Y. Ro, Jack W. Martin, Walter N. Hittelman, Reuben Lotan, Waun Ki Hong

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

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 β (RAR-β) expression in 52 baseline biopsy samples taken from premalignant oral lesions. We then studied p53 expression in 39 matched samples and RAR-β 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-μm 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-β mRNA was determined using nonradioactive in situ hybridization, and the staining intensity of RAR-β 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-β 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-β mRNA expression at baseline, whereas 22% of the patients having high p53 expression had no RAR-β expression, which suggests that patients having low p53 expression tended to lose RAR-β mRNA expression in their tissues. Eighty-three percent of patients having low p53 expression had up-regulation of RAR-β mRNA after isotretinoin therapy, compared with 22% of patients with high p53 expression (P = 0.003). We correlated baseline p53 protein expression with RAR-β modulation and clinical responses to isotretinoin therapy. The patients with low p53 protein expression at baseline and up-regulation of RAR-β 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-β or with high p53 expression and up-regulation of RAR-β had a response rate of 50%. The patients with high p53 protein expression and either no change or down-regulation of RAR-β 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.

Original languageEnglish (US)
Pages (from-to)875-880
Number of pages6
JournalClinical Cancer Research
Volume3
Issue number6
StatePublished - Jun 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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