Comparative effects of estradiol, methyl-piperidino-pyrazole, raloxifene, and ICI 182 780 on gene expression in the murine uterus.
Comparative effects of estradiol, methyl-piperidino-pyrazole, raloxifene, and ICI 182 780 on gene expression in the murine uterus.
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DOI：
10.1677/jme-08-0029
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发表时间：
2008-10
影响因子：
3.5
通讯作者：
Rosenfeld CS
中科院分区：
文献类型：
--
作者：
Davis AM;Mao J;Naz B;Kohl JA;Rosenfeld CS
选择性雌激素受体调节剂（SERM）可能有助于治疗各种子宫内膜疾病，包括子宫内膜癌，因为它们可以阻止雌激素的一些有害作用。目前尚不清楚每种 SERM 是否调节独特的基因子集，如果是的话，SERM 和 17β-雌二醇的组合是否对基因表达具有累加或协同作用。我们使用 Affymetrix Mouse Genome 430 2.0 短寡聚体阵列进行微阵列分析，以确定接受雌二醇（低剂量和高剂量）、甲基哌啶吡唑 (MPP)、ICI 182 780、雷洛昔芬以及高剂量雌二醇与 SERM 和二甲基吡啶之一的组合治疗的卵巢切除小鼠子宫中的基因表达变化 亚砜 (DMSO) 车辆控制。九种治疗分为两组，一组为 MPP、雷洛昔芬和高剂量雌二醇，第二组为低剂量雌二醇、ICI + 雌二醇、ICI、MPP + 雌二醇和雷洛昔芬 + 雌二醇。令人惊讶的是，与每种单独治疗相比，高剂量雌二醇与 SERM 相结合显着增加了受调控基因的数量（P<0.02）。通过定量 (Q)RT-PCR 对雌二醇和 SERM 处理的小鼠子宫中选定基因的表达进行分析，总体上支持了微阵列结果。对于一些癌症相关基因，包括 Klk1、Ihh、Cdc45l 和 Cdca8，MPP 或雷洛昔芬与雌二醇联合给药比单独使用雌二醇导致更高的表达（P<0.05）。相比之下，与 MPP 和雷洛昔芬治疗相比，IC1182 780 抑制了更多控制 DNA 复制的基因。因此，IC1182 780 在治疗雌激素诱发的女性子宫内膜癌方面可能优于 MPP 和雷洛昔芬。
Selective estrogen receptor modulators (SERMs) are potentially useful in treating various endometrial disorders, including endometrial cancer, as they block some of the detrimental effects of estrogen. It remains unclear whether each SERM regulates a unique subset of genes and, if so, whether the combination of a SERM and 17β-estradiol has an additive or synergistic effect on gene expression. We performed microarray analysis with Affymetrix Mouse Genome 430 2.0 short oligomer arrays to determine gene expression changes in uteri of ovariectomized mice treated with estradiol (low and high dose), methyl-piperidino-pyrazole (MPP), ICI 182 780, raloxifene, and combinations of high dose of estradiol with one of the SERM and dimethyl sulfoxide (DMSO) vehicle control. The nine treatments clustered into two groups, with MPP, raloxifene, and high dose of estradiol in one, and low dose of estradiol, ICI + estradiol, ICI, MPP + estradiol, and raloxifene + estradiol in the second group. Surprisingly, combining a high dose of estradiol with a SERM markedly increased (P<0.02) the number of regulated genes compared with each individual treatment. Analysis of expression for selected genes in uteri of estradiol and SERM-treated mice by quantitative (Q)RT-PCR generally supported the microarray results. For some cancer-associated genes, including Klk1, Ihh, Cdc45l, and Cdca8, administration of MPP or raloxifene with estradiol resulted in greater expression than estradiol alone (P<0.05). By contrast, IC1182 780 suppressed more genes governing DNA replication compared with MPP and raloxifene treatments. Therefore, IC1182 780 might be superior to MPP and raloxifene to treat estrogen-induced endometrial cancer in women.