Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark; Swedish University of Agricultural Sciences, Department of Biomedical Sciences and Veterinary Public Health, P.O. Box 7028, SE-750 07 Uppsala, Sweden.
Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
J Steroid Biochem Mol Biol. 2018 Mar;177:171-178. doi: 10.1016/j.jsbmb.2017.06.003. Epub 2017 Jun 10.
A majority of estrogen receptor positive (ER+) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER+ breast cancers. It has been reported that 1α,25-dihydroxyvitamin D down-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, 1α,25-dihydroxyvitamin D has also been reported to down-regulate the expression of estrogen receptor α (ERα), the main mediator of ER signaling. This study reports a novel transcription factor critical to 1α,25-dihydroxyvitamin D-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the 1α,25-dihydroxyvitamin D-mediated down-regulation of CYP19A1 and ERα gene expression in human MCF-7 breast cancer cells and found that Williams syndrome transcription factor (WSTF) plays a key role by binding to the promoters of CYP19A1 and ERα. Although sometimes reported as an inhibitor of gene expression, we found that WSTF acts as an activator of the promoter activity of both CYP19A1 and ERα. Silencing of WSTF by siRNA transfection resulted in decreased aromatase-dependent cell growth as well as decreased ER signaling in the cells. When cells were treated with 1α,25-dihydroxyvitamin D, WSTF was dissociated from the promoters and the promoter activities of CYP19A1 and ERα were decreased. We have measured the expression of WSTF in ER-positive tumor-samples from breast cancer patients and found that WSTF is expressed in the majority of the investigated samples and that the expression is higher in cancer tissue than in normal tissue. However, we were not able to show any significant association between the WSTF expression in the tumor and the disease free and overall survival in this patient group who have received adjuvant tamoxifen treatment, nor between the WSTF expression and the expression of ERα, progesterone receptor or HER2. The major conclusions of this study are that WSTF acts as an activator of ER signaling in MCF-7 breast cancer cells, that this action can be inhibited by 1α,25-dihydroxyvitamin D, and that the expression of WSTF is higher in breast cancer tissue than in normal tissue. WSTF may by a new target for treatment of estrogen-dependent breast cancer cell growth.
大多数雌激素受体阳性（ER+）乳腺癌的生长受雌激素刺激。因此，抑制 ER 信号通路的能力对于 ER+乳腺癌的当前治疗至关重要。据报道，1α,25-二羟维生素 D 下调 CYP19A1 基因的表达，该基因编码催化雌二醇合成的芳香酶酶。此外，1α,25-二羟维生素 D 也被报道下调雌激素受体α（ERα）的表达，ERα 是 ER 信号的主要介质。本研究报告了一种新型转录因子，该转录因子对于 MCF-7 乳腺癌细胞中 1α,25-二羟维生素 D 介导的雌激素信号调节至关重要。我们研究了 1α,25-二羟维生素 D 介导的人 MCF-7 乳腺癌细胞中 CYP19A1 和 ERα 基因表达下调的分子机制，发现威廉姆斯综合征转录因子（WSTF）通过与 CYP19A1 和 ERα 的启动子结合而发挥关键作用。尽管有时被报道为基因表达的抑制剂，但我们发现 WSTF 作为 CYP19A1 和 ERα 启动子活性的激活剂。用 siRNA 转染沉默 WSTF 会导致细胞中依赖芳香酶的细胞生长减少以及 ER 信号减少。当用 1α,25-二羟维生素 D 处理细胞时，WSTF 从启动子解离，CYP19A1 和 ERα 的启动子活性降低。我们测量了 ER 阳性乳腺癌患者肿瘤样本中的 WSTF 表达，发现 WSTF 在大多数研究样本中表达，并且在癌组织中的表达高于正常组织。然而，我们无法显示在接受辅助他莫昔芬治疗的患者组中，肿瘤中 WSTF 的表达与无病生存期和总生存期之间存在任何显著关联，也无法显示 WSTF 表达与 ERα、孕激素受体或 HER2 表达之间存在任何显著关联。本研究的主要结论是，WSTF 作为 MCF-7 乳腺癌细胞中 ER 信号的激活剂发挥作用，这种作用可以被 1α,25-二羟维生素 D 抑制，并且 WSTF 在乳腺癌组织中的表达高于正常组织。WSTF 可能是治疗雌激素依赖性乳腺癌细胞生长的新靶标。
