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

Background: Chemoprevention of breast cancer is an active area of investigation. Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g., troglitazone) and retinoids are able to inhibit the growth of breast cancer cells, Troglitazone mediates its action via peroxisome proliferator activated receptor gamma (PPAR gamma). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent the induction of 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 organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha) and LG10068 (ligand for retinoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RAR alpha. and RXR alpha) and PPAR gamma was determined by western blot analysis. Statistical significance was determined by generalized chisquared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sided, Results: Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) markedly inhibited the development of mammary lesions (both P values <.05); however, together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to inhibit 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 mammary lesions. The expression of PPAR gamma and RXR alpha remained unchanged with the various treatments, whereas the expression of RAR alpha was substantially reduced after treatment with the combination of retinoic acid and troglitazone. Conclusions: To our knowledge, this is the first report showing the possibility of a PPAR gamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.