Expression of oestrogen receptors, ERα, ERβ, and ERβ variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERα
Expression of oestrogen receptors, ERα, ERβ, and ERβ variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERα
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DOI：
10.1186/1471-2407-9-330
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发表时间：
2009-09-16
期刊：
影响因子：
3.8
通讯作者：
Saunders, Philippa T. K.
中科院分区：
文献类型：
--
作者：
Collins, Frances;MacPherson, Sheila;Saunders, Philippa T. K.
背景：子宫内膜癌是最常见的妇科恶性肿瘤；风险因素包括暴露于雌激素和高体重指数。与正常子宫内膜相比，子宫内膜癌中参与雌激素和前列腺素（PG）生物合成的酶的表达通常更高。雌激素结合由不同基因编码的两种受体（内质网α和内质网β）中的一种。全长受体作为配体激活的转录因子；还描述了缺乏配体结合结构域的ER β剪接变体异构体。pg通过结合特定的g蛋白偶联受体以自分泌或旁分泌的方式起作用。方法：采用qRTPCR、单免疫组化和双免疫组化的方法，比较ⅰ期子宫内膜腺癌（G1）、中度（G2）和低分化（G3）（每组10例）中er、孕酮受体（PR）和环氧化酶-2 （COX-2）的表达。我们使用子宫内膜腺癌细胞系研究了PGF2 α对ER和pr表达的影响。结果：全长ER β (ER β 1)和两种ER β变体（ER β 2, ER β 5）在子宫内膜癌中表达，无论级别如何，这些蛋白都免疫定位到上皮和间质室的细胞核中。COX-2的免疫表达在ER α（阴性/低）的细胞中最为强烈。PR在子宫内膜腺癌（Ishikawa）细胞系和组织中的表达与ER α大致相似。用PGF2 α治疗腺癌细胞可降低ER α的表达，但对ER β 1无影响。与PGF2 α孵育的细胞在与E2孵育时不能增加PR mRNA的表达。结论：我们证实了ER β 5蛋白在1期子宫内膜腺癌中表达。三种ER β变体的表达，包括全长蛋白，不依赖于等级，大多数低分化癌症细胞是ER β (pos)/ER α（阴性）。我们发现COX-2及其产物PGF2 α与ER α和PR表达之间存在联系的证据，这为这种疾病中类固醇和PG信号通路之间的串扰提供了新的思路。
Background: Endometrial cancer is the most common gynaecological malignancy; risk factors include exposure to oestrogens and high body mass index. Expression of enzymes involved in biosynthesis of oestrogens and prostaglandins (PG) is often higher in endometrial cancers when compared with levels detected in normal endometrium. Oestrogens bind one of two receptors (ER alpha and ER beta) encoded by separate genes. The full-length receptors function as ligand-activated transcription factors; splice variant isoforms of ER beta lacking a ligand-binding domain have also been described. PGs act in an autocrine or paracrine manner by binding to specific G-protein coupled receptors.Methods: We compared expression of ERs, progesterone receptor ( PR) and cyclooxygenase-2 (COX-2) in stage 1 endometrial adenocarcinomas graded as well (G1), moderately (G2) or poorly (G3) differentiated (n >= 10 each group) using qRTPCR, single and double immunohistochemistry. We used endometrial adenocarcinoma cell lines to investigate the impact of PGF2 alpha on expression of ERs and PR.Results: Full length ER beta (ER beta 1) and two ER beta variants (ER beta 2, ER beta 5) were expressed in endometrial cancers regardless of grade and the proteins were immunolocalised to the nuclei of cells in both epithelial and stromal compartments. Immunoexpression of COX-2 was most intense in cells that were ER alpha(neg/low). Expression of PR in endometrial adenocarcinoma (Ishikawa) cell lines and tissues broadly paralleled that of ER alpha. Treatment of adenocarcinoma cells with PGF2 alpha reduced expression of ER alpha but had no impact on ER beta 1. Cells incubated with PGF2 alpha were unable to increase expression of PR mRNA when they were incubated with E2.Conclusion: We have demonstrated that ER beta 5 protein is expressed in stage 1 endometrial adenocarcinomas. Expression of three ER beta variants, including the full-length protein is not grade-dependent and most cells in poorly differentiated cancers are ER beta(pos)/ER alpha(neg). We found evidence of a link between COX-2, its product PGF2 alpha, and expression of ER alpha and PR that sheds new light on the cross talk between steroid and PG signalling pathways in this disease.