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Research Articles: Therapeutics, Targets, and Development

Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis

Children's Hospital Oakland Research Institute, Oakland, California

Requests for reprints: Po-Lin So, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Phone: 510-438-3885 ext. 4213; Fax: 510-450-7947. E-mail: pso{at}chori.org

Abstract

Basal cell carcinoma (BCC) is the most common human cancer. Patients with basal cell nevus syndrome (Gorlin syndrome) are highly susceptible to developing many BCCs as a result of a constitutive inactivating mutation in one allele of PATCHED 1, which encodes a tumor suppressor that is a major inhibitor of Hedgehog signaling. Dysregulated Hedgehog signaling is a common feature of both hereditary and sporadic BCCs. Recently, we showed remarkable anti-BCC chemopreventive efficacy of tazarotene, a retinoid with retinoic acid receptor (RAR) β/ specificity, in Ptch1+/- mice when treatment was commenced before carcinogenic insults. In this study, we assessed whether the effect of tazarotene against BCC carcinogenesis is sustained after its withdrawal and whether tazarotene is effective against preexisting microscopic BCC lesions. We found that BCCs did not reappear for at least 5 months after topical drug treatment was stopped and that already developed, microscopic BCCs were susceptible to tazarotene inhibition. In vitro, tazarotene inhibited a murine BCC keratinocyte cell line, ASZ001, suggesting that its effect in vivo is by direct action on the actual tumor cells. Down-regulation of Gli1, a target gene of Hedgehog signaling and up-regulation of CRABPII, a target gene of retinoid signaling, were observed with tazarotene treatment. Finally, we investigated the effects of topical applications of other retinoid-related compounds on BCC tumorigenesis in vivo. Tazarotene was the most effective of the preparations studied, and its effect most likely was mediated by RAR activation. Furthermore, inhibition of basal RAR signaling in the skin promoted BCC carcinogenesis, suggesting that endogenous RAR signaling restrains BCC growth. [Mol Cancer Ther 2008;7(5):1275–84]

Grant support: NIH grants CA81888 and CA109584 (E.H. Epstein, Jr.).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 6/07; revised 1/29/08; accepted 2/ 2/08.