Estrogenic actions in human breast carcinoma : analyses for expression and regulation of the estrogen responsive genes

为了更好地了解雌激素在人类乳腺癌中的作用，我研究了乳腺癌组织中雌激素反应基因的表达和调控。我首先在20个乳腺癌组织中进行了激光捕获显微切割/微阵列分析。从这些结果中，我选择了以下基因作为可能的雌激素作用的有效调节因子，并进一步研究了这些基因在乳腺癌中的生物学和临床意义。1. Efp：Efp在73%的乳腺癌组织中免疫定位。Efp免疫反应性与雌激素受体（ER）α和淋巴结转移状态呈正相关，是乳腺癌患者的独立预后因素。这些结果表明Efp与雌激素介导的乳腺癌生长密切相关。2.ERR α：ERRα是一个与ERα相关的基因，属于核孤儿受体。乳腺癌组织中ERα与雌激素反应相关基因之间存在显著的相关性，但部分雌激素反应相关基因的雌激素反应相关性因ERRα的状态而消失，提示ERRα可能对雌激素作用有调节作用。ER α免疫反应阳性率与乳腺癌患者复发风险和不良临床结局显著相关。3.39%的乳腺癌组织中检测到PPAR γ：PPARγ免疫反应阳性，且与ERα的状态显著相关。配体介导的PPARγ激活显著抑制雌激素介导的乳腺癌细胞MCF-7中的ERE反式激活。在微阵列分析中，在33%的雌激素应答基因中检测到雌激素介导的mRNA表达被PPARγ抑制。这些结果表明，在ER阳性乳腺癌中，PPARγ也调节雌激素样作用。

In order to obtain a better understanding of estrogenic actions in human breast carcinomas, I have examined expression and regulation of estrogen responsive genes in breast carcinoma tissues. I first performed laser capture microdissection/microarray analyses in 20 breast carcinoma tissues. From these results, I selected following genes as possibly potent regulators of the estrogenic actions, and I further examined the biological and clinical significance of these in breast carcinomas.1.Efp : Efp was immunolocalized in 73% of breast carcinoma tissues. Efp immunoreactivity was positively associated with estrogen receptor (ER)α and lymph node status, and was an independent prognostic factor for breast carcinoma patients. These results suggest that Efp is closely involved in a estrogen-mediated breast cancer growth.2.ERRα : ERRα was previously identified as a gene related to ERα, and belongs to a class of nuclear orphan receptor. Significant associations were detected between ERα and ERE-containing estrogen responsive genes in breast carcinoma tissues, but the association was vanished in a part of ERE-containing estrogen responsive genes according to the ERRα-status, suggesting a possible modulation of estrogenic actions by ERRα. ERRα immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome of the patients.3.PPARγ : PPARγ immunoreactivity was detected in 39% of breast carcinoma tissues, and was significantly associated with the status of ERα. Ligand-mediated PPARγ activation significantly inhibited estrogen-mediated ERE transactivation in MCF-7 breast carcinoma cells. in microarray analysis, inhibition of estrogen-mediated mRNA expression by PPARγ was detected in 33% of estrogen-responsive genes. These results suggest that PPARγ is also modulates estrogenic actions in ER-positive breast carcinomas.