The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression
The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression
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DOI：
10.1158/0008-5472.can-06-2399
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Bishop-Bailey, David
中科院分区：
文献类型：
--
作者：
Swales, Karen E.;Korbonits, Marta;Bishop-Bailey, David
胆汁酸在乳腺囊肿和患有乳腺癌的绝经后妇女的血浆中含量很高。法尼醇 X 受体 (FXR) 是调节胆汁酸稳态的核受体超家族的成员。 FXR在正常乳腺组织和肿瘤乳腺组织中均检测到，在正常乳腺导管上皮细胞和浸润性导管癌细胞中高表达。 FXR 也存在于人乳腺癌细胞 MCF-7 和 MDA-MB-468 中。高浓度配体激活 FXR 诱导 MCF-7 和 MDA-MB-468 凋亡。在对活力没有直接影响的较低浓度下，FXR 激动剂 GW4064 诱导 FXR 靶基因、小异二聚体伴侣 (SHP)、肠胆汁酸结合蛋白和多药耐药相关蛋白 2 (MBP-2) 的 mRNA 表达，并抑制 SHP 靶基因芳香酶的表达。与 MRP-2 相比，乳腺癌靶基因 MDR-3、MRP-1 和溶质载体转运蛋白 7A5 的 mRNA 减少。尽管多药耐药转运蛋白受到调节并且是已知的 FXR 靶基因，但 GW4064 对抗癌药物紫杉醇诱导的细胞死亡没有影响。我们的研究结果首次表明 FXR 在乳腺癌组织中表达，并且具有可用于治疗乳腺癌的多种特性。
Bile acids are present at high concentrations in breast cysts and in the plasma of postmenopausal women with breast cancer. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. FXR was detected in normal and tumor breast tissue, with a high level of expression in ductal epithelial cells of normal breast and infiltrating ductal carcinoma cells. FXR was also present in the human breast carcinoma cells, MCF-7 and MDA-MB-468. Activation of FXR by high concentrations of ligands induced MCF-7 and MDA-MB-468 apoptosis. At lower concentrations that had no direct effect on viability, the FXR agonist GW4064 induced expression of mRNA for the FXR target genes, small heterodimer partner (SHP), intestinal bile acid binding protein, and multidrug resistance-associated protein 2 (MBP-2), and repressed the expression of the SHP target gene aromatase. In contrast to MRP-2, mRNA for the breast cancer target genes MDR-3, MRP-1, and solute carrier transporter 7A5 were decreased. Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel. Our findings show for the first time that FXR is expressed in breast cancer tissue and has multiple properties that could be used for the treatment of breast cancer.