Peroxisome proliferator-activated receptor gamma ligands inhibit estrogen biosynthesis in human breast adipose tissue: Possible implications for breast cancer therapy

Estrogen biosynthesis is catalyzed by aromatase cytochrome P-450 (the produ ct of the CYP19 gene). Adipose tissue is the major site of estrogen biosynt hesis in postmenopausal women, with the local production of estrogen in bre ast adipose tissue implicated in the development of breast cancer, In human adipose tissue, aromatase is primarily expressed in the mesenchymal stroma l cells and is a marker of the undifferentiated preadipocyte phenotype. Aro matase expression in adipose tissue is regulated via the distal promoter I. 4, under the control of glucocorticoids and class I cytokines such as onco statin XI, interleukin 6, and interleukin II, as well as tumor necrosis fac tor ct. These cytokines, which are expressed in adipose, also inhibit adipo cyte differentiation. Therefore, we hypothesized that factors which stimula te adipocyte differentiation should inhibit aromatase expression. These fac tors include synthetic peroxisome proliferator-activated receptor gamma (PP AR gamma) Ligands such as thiazolidinediones, e.g, troglitaxone and rosigli tazone (BRL49653) and the endogenous PPAR gamma ligand 15-deoxy-Delta(12,14 )-prostaglandin J(2). We have demonstrated bg measurement of aromatase acti vity and by reverse transcription-PCR/Southern blotting that these PPAR gam ma ligands inhibit aromatase expression in cultured breast adipose stromal cells stimulated with oncostatin hi or tumor necrosis factor cu plus dexame thasone in a concentration-dependent manner, whereas a metabolite of trogli tazone that does not activate PPAR gamma has no effect. We have also shown that troglitazone inhibits luciferase activity of reporter constructs conta ining various lengths of the upstream region of promoter I.4 transfected in to mouse 3T3-L1 preadipocyte mesenchymal cells, Whereas the troglitazone me tabolite does not. Because local estrogen production in breast fat is impli cated 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.