Transcription factors of estrogen receptor alpha in human endometrium

雌激素受体α(ER-α)与雌二醇一起，通过其靶分子在控制细胞生长和分化中发挥重要作用。乳腺癌细胞中的表皮生长因子、胰岛素样生长因子-I通过磷脂酰肌醇3-激酶(PI3K)/α信号转导通路调节ER-AKT的活性。为了阐明ERα在子宫内膜细胞中的功能是如何调节的，我们检测了与ERα磷酸化相关的分子。结果发现，磷酸化p-Aktl/2/3(Thr308)在增殖期表达增加，而在分泌期表达降低。相反，p-Aktl/2/3(Thr473)在增殖期表达较低，进入分泌期后表达较高。对磷酸化的ERα的观察表明，p-erα(Ser104)的表达是恒定的，而p-erα(Ser118)的表达遵循与p-Aktl/2/3(Thr308)类似的周期模式。磷酸化ERα和Akt在未处理的Ishikawa细胞中的表达模式与正常子宫内膜细胞相似，但p-erα(Ser167)仅在Ishikawa细胞中表达。用多种针对ErbB/PI3K/Akt通路的抑制剂处理后，发现p-erα(Ser118)和p-erα(Ser168)的表达受到抑制。进一步的研究表明，抑制PI3K或AKT，而不是ErbB，可以诱导细胞凋亡，而雌激素的加入可以拮抗这一作用，表明参与了线粒体途径。PI3K/AKT在正常和癌变子宫内膜细胞中的功能差异有待进一步研究。

Estrogen receptor alpha (ERα), together with estradiol plays a critical role through its target molecules in control of cell growth and differentiation. The activities of ERα itself can be modulate by epidermal growth factor (EGF), insulin-like growth factor-I via the phosphatidylinostitol 3-kinase (PI3K)/AKT pathway in breast cancer cells. To clarify how ERα functions are regulated in endometrial cells, molecules related to phosphorylation of ERα were examined. It was found that the expression of phosphorylated p-Aktl/2/3 (Thr 308) was increased during the proliferative phase, but decreased in the secretory phase. On the contrary, the expression of p-Aktl/2/3 (Thr 473) was lower in the proliferative phase, but higher after entering secretory phase. Observation of the phosphorylated Erα revealed that while the expression of p-Erα (Ser 104) was constant, p-Erα (Ser 118) was shown following a cyclic pattern like that of the p-Aktl/2/3 (Thr 308).To reveal difference between normal and cancerous glandular cells, cultured Ishikawa cells were first examined immunohistochmically. The expression pattern of phosphorylated ERα and Akt in the untreated Ishikawa cells was similar to that of the normal endometrial cells, except that the expression of p-Erα (Ser 167) was only found in Ishikawa cells. Following treatment with various inhibitors that specifically target the ErbB/PI3K/Akt pathway, it was found out that the expression of p-Erα (Ser 118) and p-Erα (Ser 168) was inhibited. Further examination showed that inhibition of PI3K or AKT, rather than ErbB could induce apoptosis that could be antagonized by the addition of estrogen, indicating a mitochondrial pathway is involved. Further study is necessary to explore functional difference of PI3K/AKT in normal and cancerous endometrial cells.