A nuclear receptor system constituted by RAR and RXR induces aromatase activity in MCF-7 human breast cancer cells

Estrogen is the most important endocrine hormone that stimulates the growth of hormone-dependent breast cancer. The biosynthesis of estrogens in breast tissue is catalyzed by cytochrome P450 aromatase (P450arom). The expression of P450arom is controlled by the tissue- or cell-specific promoters of CYP 19 gene. The roles of nuclear receptor systems for the aromatase activity in breast cancer cells have not yet been fully investigated. In the present study, we investigated the effects of a nuclear receptor system constituted by retinoid X receptor (RXR) and its heterodimer partner on the aromatase activity in a cultured MCF-7 human breast cancer cell line, using each selective ligand for retinoic acid receptor (RAR) (TTNPB), RXR (LG100268), PPARgamma (troglitazone), and vitamin D(3) receptor (vitamin D(3)). The treatment of the cells with TTNPB or LG100268 alone for 2 days increased slightly the aromatase activity, but the increases were not statistically significant in comparison to the control. However, the combined treatment with TTNPB (10(-7) M) and LG100268 (10(-7) M) caused a dramatic stimulation of the aromatase activity. The treatment with other ligands had little or no effect on the aromatase activity. The stimulation of the aromatase activity by TTNPB plus LG100268 was dose-dependent, and a maximum stimulation was observed at 10(-7) M in both compounds. In addition, the increase in the aromatase activity was accompanied by an increase in the P450arom mRNA levels determined by RT-PCR in MCF-7 cells. The increase in the P450arom transcript was also found to be related to the specific usage of promoter 1a of the CYP 19 gene based on the analysis using RT-PCR. This is the first demonstration that a nuclear receptor system constituted by a RAR:RXR heterodimer is involved in the regulation of aromatase activity in MCF-7 breast cancer cells.