Mu Y M, Yanase T, Nishi Y, Hirase N, Goto K, Takayanagi R, Nawata H
The Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
Mol Cell Endocrinol. 2000 Aug 30;166(2):137-45. doi: 10.1016/s0303-7207(00)00273-2.
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.
雌激素是刺激激素依赖性乳腺癌生长的最重要的内分泌激素。乳腺组织中雌激素的生物合成由细胞色素P450芳香化酶（P450arom）催化。P450arom的表达受CYP 19基因的组织或细胞特异性启动子控制。核受体系统在乳腺癌细胞中对芳香化酶活性的作用尚未得到充分研究。在本研究中，我们使用视黄酸受体（RAR）（TTNPB）、视黄醇X受体（RXR）（LG100268）、过氧化物酶体增殖物激活受体γ（PPARγ）（曲格列酮）和维生素D3受体（维生素D3）的每种选择性配体，研究了由视黄醇X受体（RXR）及其异二聚体伴侣组成的核受体系统对培养的MCF-7人乳腺癌细胞系中芳香化酶活性的影响。单独用TTNPB或LG100268处理细胞2天，芳香化酶活性略有增加，但与对照组相比，增加无统计学意义。然而，TTNPB（10^-7 M）和LG100268（10^-7 M）联合处理导致芳香化酶活性显著增强。用其他配体处理对芳香化酶活性几乎没有影响。TTNPB加LG100268对芳香化酶活性的刺激呈剂量依赖性，两种化合物在10^-7 M时均观察到最大刺激。此外，芳香化酶活性的增加伴随着通过RT-PCR测定的MCF-7细胞中P450arom mRNA水平的增加。基于RT-PCR分析，还发现P450arom转录本的增加与CYP 19基因启动子1a的特定使用有关。这是首次证明由RAR:RXR异二聚体组成的核受体系统参与MCF-7乳腺癌细胞中芳香化酶活性的调节。
