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 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.
Mehta
R G
RG
Department of Surgical Oncology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
Williamson
E
E
Patel
M K
MK
Koeffler
H P
HP
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002273:Carcinogens; D002839:Chromans / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008024:Ligands; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control*; D011374:Progesterone / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D000077288:Troglitazone; D000097768:Retinoic Acid Receptor gamma
D015127:9,10-Dimethyl-1,2-benzanthracene; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D002839:Chromans; D004958:Estradiol; D008024:Ligands; D011374:Progesterone; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014212:Tretinoin; D000077288:Troglitazone; D000097768:Retinoic Acid Receptor gamma; C407368:LG10068; C000607072:Rara protein, mouse