Liu Dingxie
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bluewater Biotech LLC, Berkeley Heights, NJ, USA.
FEBS J. 2016 Aug;283(16):3115-33. doi: 10.1111/febs.13798. Epub 2016 Jul 24.
The associations of estrogen receptor (ER) and progesterone receptor (PR) pathways with the prognosis of colorectal cancer (CRC) are still controversial. The aim of this study was to readdress these issues by introducing a gene signature-based approach to semiquantitate pathway activity. In this approach, the ER and PR pathway activities in CRC were computed based on the expression profiles of the signature genes of ER and PR pathways, respectively. The results showed that the ER pathway activity was progressively significantly decreased from normal colorectal mucosa, colorectal adenoma to CRC. ER pathway signaling was a favorable factor for the presence of microsatellite stability (MSS) in CRC in seven cohorts tested, while was an unfavorable factor for cancer recurrence in all four CRC cohorts tested (n = 1122; overall HR: 0.311, 95% CI: 0.199-0.488, P < 0.001). Subset stratification in stage II patients showed that ER pathway remained significantly inversely associated with recurrence. PR pathway was also suppressed in colorectal tumors and inversely associated with recurrence of CRC, but to a much lesser extent than ER pathway. Moreover, the inverse association of PR pathway with cancer recurrence was more likely observed in CRC with high ER pathway activity, suggesting the interactions between the two pathways. PR pathway was not associated with MSS in CRC, but it was more significant than ER pathway associated with advance cancer stages and cancer response to adjuvant chemotherapy. These results suggested the potential application of the gene signatures of ER and PR pathways, especially the former, as novel markers for prognosis and management of CRC.
雌激素受体（ER）和孕激素受体（PR）通路与结直肠癌（CRC）预后的相关性仍存在争议。本研究的目的是通过引入基于基因特征的方法来半定量通路活性，重新探讨这些问题。在这种方法中，CRC中ER和PR通路的活性分别基于ER和PR通路特征基因的表达谱进行计算。结果表明，从正常结直肠黏膜、结直肠腺瘤到CRC，ER通路活性逐渐显著降低。在7个测试队列中，ER通路信号是CRC中微卫星稳定性（MSS）存在的有利因素，而在所有4个测试的CRC队列中（n = 1122；总体风险比：0.311，95%置信区间：0.199 - 0.488，P < 0.001），它是癌症复发的不利因素。II期患者的亚组分层显示，ER通路与复发仍显著呈负相关。PR通路在结直肠肿瘤中也受到抑制，与CRC复发呈负相关，但程度远小于ER通路。此外，在ER通路活性高的CRC中，更可能观察到PR通路与癌症复发的负相关，这表明两条通路之间存在相互作用。PR通路与CRC中的MSS无关，但与晚期癌症阶段和癌症对辅助化疗的反应相关，比ER通路更显著。这些结果表明，ER和PR通路的基因特征，尤其是前者，作为CRC预后和管理的新标志物具有潜在应用价值。
