A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions

Background: Chemoprevention of breast cancer is an active area of investiga tion. Recent in vivo and in vitro studies have shown that thiazolidinedione s (e.g., troglitazone) and retinoids are able to inhibit the growth of brea st cancer cells, Troglitazone mediates its action via peroxisome proliferat or activated receptor gamma (PPAR gamma). We evaluated the ability of trogl itazone, alone or in combination with retinoids, to prevent the induction o f preneoplastic lesions by 7,12-dimethylbenz[a]anthracene (DMBA) in a mouse mammary gland organ culture model. Methods: Mammary glands of BALB/c mice were treated with DMBA (2 mu g/ mL) to induce preneoplastic lesions in orga n culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha) and LG10068 (ligand for ret inoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RAR alpha. and RX R alpha) and PPAR gamma was determined by western blot analysis. Statistica l significance was determined by generalized chisquared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sid ed, Results: Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) mark edly inhibited the development of mammary lesions (both P values <.05); how ever, together they did not enhance the effectiveness of the other. In cont rast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to in hibit development of these lesions, but a combination of LG10068 (at 10(-8) M) and troglitazone (at 10(-5) M or 10(-6) M) almost completely inhibited (by 85% and 100%, respectively; both P values <.05) the development of mamm ary lesions. The expression of PPAR gamma and RXR alpha remained unchanged with the various treatments, whereas the expression of RAR alpha was substa ntially reduced after treatment with the combination of retinoic acid and t roglitazone. Conclusions: To our knowledge, this is the first report showin g the possibility of a PPAR gamma ligand having chemopreventive activity. F urthermore, an RXR-selective retinoid, LG10068, appears to enhance this act ivity.