Title Page Molecular Pathways: Current Role and Future Directions of the Retinoic Acid Pathway In Cancer Prevention and Treatment Authors:

Retinoids and their naturally metabolized and synthetic products (e.g. all-trans retinoic acid, 13cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (α, β, γ), which are transcriptional and homeostatic regulators whose functions are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their utility in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high-risk for breast cancer. Ongoing phase 3 randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARβ. Robust evaluation of RARβ and downstream genes may permit optimized use of retinoids in the solid tumor arena. Research. on January 21, 2018. © 2013 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on January 15, 2013; DOI: 10.1158/1078-0432.CCR-12-3175