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 (PPARgamma). 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 microg/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 (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared 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 PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha 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 PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.
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 (PPARgamma). 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 microg/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 (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared 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 PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha 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 PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.
Authors: Eunjung Lee; Chris Hsu; David Van den Berg; Giske Ursin; Woon-Puay Koh; Jian-Min Yuan; Daniel O Stram; Mimi C Yu; Anna H Wu Journal: Cancer Epidemiol Biomarkers Prev Date: 2012-02-01 Impact factor: 4.254
Authors: Gaurav Luther; Richard Rames; Eric R Wagner; Gaohui Zhu; Qing Luo; Yang Bi; Stephanie H Kim; Jian-Li Gao; Enyi Huang; Ke Yang; Linyuan Wang; Xing Liu; Mi Li; Ning Hu; Yuxi Su; Xiaoji Luo; Liang Chen; Jinyong Luo; Rex C Haydon; Hue H Luu; Lan Zhou; Tong-Chuan He Journal: Trends Cancer Res Date: 2010
Authors: Jie Zhou; Wei Zhang; Bing Liang; Mathew C Casimiro; Diana Whitaker-Menezes; Min Wang; Michael P Lisanti; Susan Lanza-Jacoby; Richard G Pestell; Chenguang Wang Journal: Int J Biochem Cell Biol Date: 2009-06-26 Impact factor: 5.085
Authors: Yekaterina Y Zaytseva; Xin Wang; R Chase Southard; Natalie K Wallis; Michael W Kilgore Journal: Mol Cancer Date: 2008-12-05 Impact factor: 27.401