Retinoid, RARp-selective

Identification of RARp-selective retinoids has been challenging. Three that have been reported are the AHPN analog 6-[3-(l-methylcyclohexyl)-4-methoxyphenyl]-2-naphtha-lenecarboxylic acid (CD2019) [58, 64], 4-[2,2-difluoro-l-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethenyl]benzoic acid (BMS188970) [60], and 6-[4-3-(2-methyl-2-propyl)-4-(2-methyl)propyloxyphenyl]-2-naphthalenecarboxylic acid (Ro 48-2249) [63]. 

Roy, B., Taneja, R., and Chambon, P. (1995). Synergistic activation of retinoic acid (RA)-re-sponsive genes and induction of embryonal carcinoma ceU differentiation by an RA receptor a (RARa)-, RARP-, or RARy-selective ligand in combination vdth a retinoid X receptor-specific ligand. Mol. Cell. Biol. 15, 6481-6487. 

With the use of an indirect method for quantifying retinoids, namely a luciferase reporter gene construct containing two RA response elements (RAREs) from the RARp gene, Chen et al. confirmed significant RA activity in Xenopus embryos [46]. Later it was shown that the reporter construct used by Chen et al. can be activated by all-frans-RA, 9-cis-RA and synthetic ligands selective for RARs in Xenopus embryos [47]. 

Figure 1. Concentration-dependent transcriptional activation of the retinoic acid receptor subtypes a, p, and yon the (TREpal)2-tfc-CAT reporter construct in CV-1 cells by (A) RARa-selective retinoids Am580 (RARa, RARp, RARy A) and Am80 (RARa, O RARp, RARy A), and (B) RARy-selective retinoids SRI 1254 (RARa, RARP, RARy A) and AHPN (RARa, O RARp, RARy A).

To further complicate this biological-activity scheme, as well as the central importance observed for RARa and RARP in mediating RA activity in breast cancer, recent studies have demonstrated the relevance of the third member of the RAR family, RARy. This receptor also seems to play a role in controlling the growth of breast cancer cells [36], being elevated by RA treatment in several ER and ER" cells, concomitant of retinoid responsiveness [37]. These data are also confirmed by the retained biological activity of RARy-selective retinoids in comparison with RA, as observed by successive studies [38]. 

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