© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 5, 418-423,
March 1, 2000
© 2000 Oxford University Press
REPORT |
A Ligand of Peroxisome Proliferator-Activated Receptor 
, Retinoids, and Prevention of Preneoplastic Mammary Lesions
Affiliations of authors: R. G. Mehta, M. K. Patel, Department of Surgical Oncology, College of Medicine, University of Illinois, Chicago; E. Williamson, H. P. Koeffler, Hematology/Oncology Division, Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine.
Correspondence to: Rajendra G. Mehta, Ph.D., Department of Surgical Oncology, University of Illinois at Chicago, College of Medicine, 840 S. Wood St. (M/C 820), Chicago, IL 60612 (e-mail: raju{at}uic.edu).
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 
(PPAR). 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 µg/mL) to induce preneoplastic lesions in
organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for
retinoic acid receptor [RAR] 
), and LG10068 (ligand for retinoid X
receptors [RXRs]), singly or in combination, on the development of lesions were
evaluated. Expression of retinoid receptors (RAR and RXR) and
PPAR 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 PPAR and RXR remained unchanged with the various treatments, whereas the expression of RAR 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 ligand having chemopreventive activity. Furthermore, an
RXR-selective retinoid, LG10068, appears to enhance this activity.
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