Nuclear Retinoic Acid Receptor Beta as a Tool in Chemoprevention Trials

B.      Pavan; C.      Biondi; A.      Dalpiaz

Abstract

Retinoic acid (RA) and its natural and synthetic derivatives (retinoids) are important dietary factors which regulate cellular differentiation and growth, so that they are thought to be particularly effective at preventing the development of several tumours. They play this role as ligands of the RAR and RXR nuclear retinoic acid receptors, including the RA receptor isoforms alpha, beta, and gamma. These ligand-activated nuclear receptors induce the transcription of target genes by binding to RA-responsive elements in the promoter regions. Among these target genes, the RARβ gene is of great interest, being able to encode a potential tumour suppressor. It should be emphasized that most breast carcinomas and breast cancer cell lines show loss or down-regulation of RARβreceptor expression, whereas RARα and γ, as well as retinoid X receptors, appear to be variably expressed in both normal and tumour cells. It is also interesting to note that basal and RA-induced RARβ mRNA levels tend to increase with senescence of normal cells. This information provides further support for the hypothesis that genetic events involved in cellular senescence may also play a significant role in tumour suppression in humans. The aim of this review is to clarify whether expression of RARβ could be modulated by chemopreventive intervention and may therefore serve as an intermediate biomarker in chemoprevention trials for some cancers.

Keywords: Retinoic acid, RARβ, chemoprevention, senescence, differentiation, epigenetics, retinoids, HL-60 cells