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[Cancer Research 60, 1604-1608, March 15, 2000]
© 2000 American Association for Cancer Research

Endocrinology

Peroxisome Proliferator-activated Receptor {gamma} Ligands Inhibit Estrogen Biosynthesis in Human Breast Adipose Tissue: Possible Implications for Breast Cancer Therapy1

Gary L. Rubin2, Ying Zhao, Allan M. Kalus and Evan R. Simpson

Victorian Breast Cancer Research Consortium, Inc., Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168, Australia [G. L. R., E. R. S.]; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9051 [Y. Z.]; and The Plastic & Aesthetic Surgery Centre, Windsor, Victoria 3181, Australia [A. M. K.]

Estrogen biosynthesis is catalyzed by aromatase cytochrome P-450 (the product of the CYP19 gene). Adipose tissue is the major site of estrogen biosynthesis in postmenopausal women, with the local production of estrogen in breast adipose tissue implicated in the development of breast cancer. In human adipose tissue, aromatase is primarily expressed in the mesenchymal stromal cells and is a marker of the undifferentiated preadipocyte phenotype. Aromatase expression in adipose tissue is regulated via the distal promoter I.4, under the control of glucocorticoids and class I cytokines such as oncostatin M, interleukin 6, and interleukin 11, as well as tumor necrosis factor {alpha}. These cytokines, which are expressed in adipose, also inhibit adipocyte differentiation. Therefore, we hypothesized that factors which stimulate adipocyte differentiation should inhibit aromatase expression. These factors include synthetic peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands such as thiazolidinediones, e.g., troglitazone and rosiglitazone (BRL49653) and the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2. We have demonstrated by measurement of aromatase activity and by reverse transcription-PCR/Southern blotting that these PPAR{gamma} ligands inhibit aromatase expression in cultured breast adipose stromal cells stimulated with oncostatin M or tumor necrosis factor {alpha} plus dexamethasone in a concentration-dependent manner, whereas a metabolite of troglitazone that does not activate PPAR{gamma} has no effect. We have also shown that troglitazone inhibits luciferase activity of reporter constructs containing various lengths of the upstream region of promoter I.4 transfected into mouse 3T3-L1 preadipocyte mesenchymal cells, whereas the troglitazone metabolite does not. Because local estrogen production in breast fat is implicated in breast cancer development in postmenopausal women, the actions of PPAR{gamma} ligands suggest that they may have potential therapeutic benefit in the treatment and management of breast cancer.




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