Rexinoids and breast cancer prevention.

In this issue of Clinical Cancer Research , Li et al. investigate the chemopreventive potential of the retinoid, LG100268 (1). The application of retinoids to cancer chemoprevention has a long history which predates the identification of retinoid receptors (2, 3). Early clinical trials evaluated vitamin A derivatives, such as 13-cis-retinoic acid (13-cis-RA), all-trans retinoic acid (ATRA), and 9-cis-retinoic acid (9-cis-RA), in individuals at increased risk of developing cancer. These trials were pivotal in establishing proof of principle for human cancer chemoprevention, and moreover, showed the potential utility of retinoids in this respect. The associated toxicity, however, identified high-dose regimens of naturally occurring retinoids as unsuitable for long-term administration for cancer prevention. Increased understanding of retinoid receptor biology has facilitated the design of synthetic ligands with increased selectivity and hence decreased toxicity. Specifically, ligands selective for the retinoid X receptor subclass have been developed, the socalled rexinoids, which seem to afford equivalent or greater protection against cancer with substantially diminished toxicity. The current state of evolution of this drug class is illustrated by Li et al. (1), in this issue, who describe the chemopreventive action of the rexinoid LG100268 with respect to estrogen receptor – negative breast cancer. LG100268 markedly suppresses the formation of both invasive breast cancers and premalignant mammary lesions in rodent breast cancer models, with minimal incidence of common retinoid toxicities (1, 4–6). These studies are paving the way for testing rexinoids for breast cancer prevention.