Up-regulation of retinoic acid receptor β expression in renal cancers in vivo correlates with response to 13-cis-retinoic acid and interferon-α- 2a

Retinoic acid receptor-β (RAR-β) mRNA is not expressed by retinoid- resistant renal cancer cell lines but is present in retinoid-sensitive SK- RC-06 renal cancer cells and increases following incubation with retinoic acid (RA), suggesting that the antitumor action of RA is mediated through RAR-β (A.D. Hoffman et al., Clin. Cancer Res., 2: 1077-1082, 2996). To determine whether RAR-β expression correlates in vivo with major clinical response to patients with renal cell carcinoma (RCC) who were treated with retinoid-based therapy, we used in situ hybridization to analyze RAR-β expression in tumor specimens obtained from patients who were treated on a clinical trial with 13-cis-RA and IFN-α. Thirty-three tissue specimens were analyzed (23 pretreatment and 10 on-treatment). mRNA expression was based on staining intensity, with scores within tumor cells ranging from 0 to 2, where a score of 0 indicated absence of staining, a score of 1 indicated weak staining, and a score of 2 indicated strong staining. RAR-β expression was present in 22 of 23 (96%) pretreatment and 9 of 10 (90%) on-treatment specimens. Pretreatment levels of expression did not associate with the site of biopsy and did not predict for major clinical response to RA plus IFN-α therapy (two-sided Fisher's exact test, P = 0.826). However, an increase in the intensity of RAR-β mRNA expression was detected in four of five (80%) patients who achieved a major response but in none of the five patients with progressive disease in whom sequential biopsies were available (two-sided Fisher's exact test, P = 0.048). These data show that RAR-β transcripts increase in tumor cells of RCC patients who clinically respond to retinoid- based therapy. Retinoids that potently induce RAR-β expression should be evaluated in the treatment of advanced RCC.