Purpose

Anti-estrogen therapy may be used as a palliative treatment option in high-grade serous ovarian carcinomas (HGSC). However, clinical implementation is limited as the use of estrogen receptor (ER) protein expression by immunohistochemistry remains insufficient in predicting therapy response. To determine the accuracy of ER protein expression as a marker for ER signaling pathway activity, we aimed to correlate ER protein expression to functional ER signaling pathway activity in HGSC.

Methods

Immunohistochemical ER protein expression was visually scored using total percentages of stained tumor cells and histoscores. Subsequently, mRNA was extracted, and RT-qPCR analysis was performed. Functional ER pathway activity was assessed by a computational Bayesian model inferring ER signaling pathway activity from mRNA levels of ER-specific target genes.

Results

Our analysis of 29 HGSCs shows that neither total percentage of ER protein expression, nor ER histoscores are significantly correlated to ER signaling pathway activity (respectively, p = 0.473 and p = 0.606). Classification of HGSC into three groups based on ER histoscores 0–100 (n = 6), 101–200 (n = 15) and 201–300 (n = 8) resulted in comparable mean ER signaling pathway activity among the groups (p = 0.356). Several samples in the higher ER histoscore groups had low ER signaling pathway activity, indicating that nuclear ER protein expression is not sufficient to describe transcriptional ER activation.

Conclusion

Positive immunohistochemical ER staining is not always indicative of an active ER signaling pathway and is, therefore, a poor predictor of anti-estrogen response. Further research is needed to prove the predictive value of ER signaling pathway activity regarding anti-estrogen sensitivity in HGSC patients.

中文翻译：

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高级别浆液性卵巢癌中功能性雌激素受体信号通路活性与免疫组化雌激素受体蛋白表达的比较

目的

抗雌激素治疗可用作高级别浆液性卵巢癌 (HGSC) 的姑息治疗选择。然而，临床实施受到限制，因为通过免疫组织化学使用雌激素受体 (ER) 蛋白表达在预测治疗反应方面仍然不足。为了确定 ER 蛋白表达作为 ER 信号通路活性标志物的准确性，我们旨在将 ER 蛋白表达与 HGSC 中的功能性 ER 信号通路活性相关联。

方法

使用染色肿瘤细胞的总百分比和组织评分对免疫组织化学 ER 蛋白表达进行视觉评分。随后，提取mRNA，并进行RT-qPCR分析。通过计算贝叶斯模型评估功能性 ER 通路活性，该模型从 ER 特异性靶基因的 mRNA 水平推断 ER 信号通路活性。

结果

我们对 29 个 HGSC 的分析表明，ER 蛋白表达的总百分比和 ER 组织评分均与 ER 信号通路活性显着相关（分别为p  = 0.473 和p  = 0.606）。根据 ER 组织评分 0-100 (n = 6)、101-200 (n = 15) 和 201-300 (n = 8) 将 HGSC 分为三组，导致各组之间的平均 ER 信号通路活性相当（p  = 0.356）。较高 ER histoscore 组中的几个样本具有较低的 ER 信号通路活性，表明核 ER 蛋白表达不足以描述转录 ER 激活。

结论

阳性免疫组织化学 ER 染色并不总是表明激活的 ER 信号通路，因此是抗雌激素反应的不良预测指标。需要进一步的研究来证明 ER 信号通路活性对 HGSC 患者抗雌激素敏感性的预测价值。