This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rubin, G. L. Articles by Simpson, E. R. Search for Related Content PubMed PubMed Citation Articles by Rubin, G. L. Articles by Simpson, E. R.

Ligands for the Peroxisomal Proliferator-Activated Receptor and the Retinoid X Receptor Inhibit Aromatase Cytochrome P450 (CYP19) Expression Mediated by Promoter II in Human Breast Adipose

Victorian Breast Cancer Research Consortium Inc (G.L.R., C.D.C., C.J.S., Y.M., C.G., E.R.S.), Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia; and Department of Biochemistry and Molecular Biology (G.L.R., J.H.D., C.D.C., C.J.S., E.R.S.), Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: Evan R. Simpson, Ph.D., Prince Henry’s Institute of Medical Research, Level 4, Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: . evan.simpson{at}med.monash.edu.au

Local estrogen biosynthesis in breast adipose tissue, catalyzed by P450 aromatase, contributes to the growth of breast carcinomas. Aromatase expression is regulated by a number of alternative promoters, and in normal adipose tissue it is primarily regulated via the distal promoter I.4. However, in breast adipose containing a tumor, aromatase expression is regulated by the proximal promoter II in response to tumor-derived factors. Previously we have shown that peroxisomal proliferator-activated receptor (PPAR) ligands inhibit aromatase expression in normal breast adipose tissue mediated by promoter I.4. In the present study, we investigated the effects of the PPAR ligand troglitazone and the retinoid X receptor (RXR) ligand LG101305 on aromatase expression mediated by promoter II. In cultured human breast adipose stromal cells, troglitazone or LG101305 alone inhibited aromatase activity and expression stimulated by inducers of promoter II, in a concentration-dependent manner, and this inhibition was greater in the presence of both ligands. Reporter gene assays showed that troglitazone and LG101305 inhibit transcription from promoter II of the CYP19 gene. However, EMSAs showed that PPAR and RXR do not bind to promoter II of the CYP19 gene, indicating that PPAR- and RXR-mediated inhibition of aromatase expression via promoter II occurs through an indirect mechanism of action. Because ligands for PPAR and RXR inhibit aromatase expression in healthy breast adipose (via promoter I.4), as well as expression induced by tumor-derived factors (via promoter II), such compounds could find utility in the treatment of estrogen-dependent breast cancers.

This article has been cited by other articles:

				P. H. Brown, K. Subbaramaiah, A. P. Salmon, R. Baker, R. A. Newman, P. Yang, X. K. Zhou, R. P. Bissonnette, A. J. Dannenberg, and L. R. Howe Combination Chemoprevention of HER2/neu-Induced Breast Cancer Using a Cyclooxygenase-2 Inhibitor and a Retinoid X Receptor-Selective Retinoid Cancer Prevention Research, August 1, 2008; 1(3): 208 - 214. [Abstract] [Full Text] [PDF]

				R. Safi, A. Kovacic, S. Gaillard, Y. Murata, E. R. Simpson, D. P. McDonnell, and C. D. Clyne Coactivation of Liver Receptor Homologue-1 by Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha} on Aromatase Promoter II and Its Inhibition by Activated Retinoid X Receptor Suggest a Novel Target for Breast-Specific Antiestrogen Therapy Cancer Res., December 15, 2005; 65(24): 11762 - 11770. [Abstract] [Full Text] [PDF]

				L Hilakivi-Clarke, C Wang, M Kalil, R Riggins, and R G Pestell Nutritional modulation of the cell cycle and breast cancer Endocr. Relat. Cancer, December 1, 2004; 11(4): 603 - 622. [Abstract] [Full Text] [PDF]

				L. Gennari, R. Nuti, and J. P. Bilezikian Aromatase Activity and Bone Homeostasis in Men J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5898 - 5907. [Abstract] [Full Text] [PDF]

				J. P. Klopper, W. R. Hays, V. Sharma, M. A. Baumbusch, J. M. Hershman, and B. R. Haugen Retinoid X receptor-{gamma} and peroxisome proliferator-activated receptor-{gamma} expression predicts thyroid carcinoma cell response to retinoid and thiazolidinedione treatment Mol. Cancer Ther., August 1, 2004; 3(8): 1011 - 1020. [Abstract] [Full Text] [PDF]

				A. Kovacic, C. J. Speed, E. R. Simpson, and C. D. Clyne Inhibition of Aromatase Transcription Via Promoter II by Short Heterodimer Partner in Human Preadipocytes Mol. Endocrinol., January 1, 2004; 18(1): 252 - 259. [Abstract] [Full Text] [PDF]

				C. M. Komar and T. E. Curry Jr Inverse Relationship Between the Expression of Messenger Ribonucleic Acid for Peroxisome Proliferator-Activated Receptor {gamma} and P450 Side Chain Cleavage in the Rat Ovary Biol Reprod, August 1, 2003; 69(2): 549 - 555. [Abstract] [Full Text] [PDF]

				O. Barbier, L. Villeneuve, V. Bocher, C. Fontaine, I. P. Torra, C. Duhem, V. Kosykh, J.-C. Fruchart, C. Guillemette, and B. Staels The UDP-glucuronosyltransferase 1A9 Enzyme Is a Peroxisome Proliferator-activated Receptor alpha and gamma Target Gene J. Biol. Chem., April 11, 2003; 278(16): 13975 - 13983. [Abstract] [Full Text] [PDF]