ERβ1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer
ERβ1 inversely correlates with PTEN/PI3K/AKT pathway and predicts a favorable prognosis in triple-negative breast cancer
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DOI：
10.1007/s10549-015-3467-3
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发表时间：
2015-06
影响因子：
3.8
通讯作者：
Jin Wang;Chao Zhang;Keming Chen;Hailin Tang;Jun Tang;Cailu Song;Xiaoming Xie
中科院分区：
文献类型：
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作者：
Jin Wang;Chao Zhang;Keming Chen;Hailin Tang;Jun Tang;Cailu Song;Xiaoming Xie
与雌激素受体α（ERα）在乳腺癌中的作用相比，雌激素受体β（ERβ）的意义仍然存在争议，特别是在三阴性乳腺癌（TNBC）中。我们试图基于大规模人群研究野生型ERβ（ERβ1）在TNBC中的临床重要性，并探索参与的潜在分子途径。本研究共纳入了571例接受根治性手术的侵袭性TNBC患者。在组织芯片上进行ERβ1、pAKT、PTEN、pERK、β-catenin、EGFR、p53和E-cadherin的免疫组织化学染色。在单变量和多变量分析中评估了总生存期（OS）和无病生存期（DFS）的预后决定因素，以及无远处转移生存期（DMFS）和局部无复发生存期的风险因素。ERβ1在30.4%的肿瘤组织中呈高表达. ERβ1阳性者多为绝经后妇女，淋巴结转移率低。多因素分析显示ERβ1独立预测OS、DFS和DMFS。关于其他生物标志物，只有pAKT被确定为生存的独立阴性预测因子。ERβ1表达与pAKT和PTEN缺失呈负相关。值得注意的是，根据ERβ1/pAKT状态的进一步生存分析表明，ERβ1（+）/pAKT（-）预测TNBC的最有利预后。相反，ERβ1（-）/pAKT（+）与最差结局相关。总之，我们的研究结果表明，ERβ1独立预测TNBC的更好预后，并可能与PTEN/PI 3 K/pAKT通路相互作用。ERβ1特异性激动剂联合pAKT抑制剂的作用值得进一步研究。
In contrast to the well-established role of estrogen receptor alpha (ERα) in breast cancer, the significance of estrogen receptor beta (ERβ) remains controversial, especially in triple-negative breast cancer (TNBC). We sought to investigate the clinical importance of wild-type ERβ (ERβ1) in TNBC based on a large population, and to explore the potential molecular pathways involved in. A total of 571 patients with invasive TNBC undergoing curative surgery were included in this study. Immunohistochemical staining for ERβ1, pAKT, PTEN, pERK, β-catenin, EGFR, p53, and E-cadherin was performed on tissue microarrays. Prognostic determinants for overall survival (OS) and disease-free survival (DFS), as well as the risk factors for distant metastasis-free survival (DMFS) and locoregional recurrence-free survival, were evaluated in univariate and multivariate analyses. Overexpression of ERβ1 was detected in 30.4 % of tumor samples. Patients with ERβ1 tended to be postmenopausal, and less likely to develop lymphatic metastasis. Multivariate analysis demonstrated that ERβ1 predicted a better OS, DFS, and DMFS independently. Regarding other biomarkers, only pAKT was identified as an independent negative predictor for survival. Additionally, ERβ1 expression was inversely associated with pAKT and the loss of PTEN. Notably, further survival analysis according to status of ERβ1/pAKT indicated that ERβ1(+)/pAKT(−) predicted the most favorable prognosis for TNBC. On the contrary, ERβ1(−)/pAKT(+) was associated with the worst outcomes. In summary, our findings indicate that ERβ1 independently predicts a better prognosis for TNBC and potentially interacts with the PTEN/PI3K/pAKT pathway. The role of ERβ1-specific agonists combined with the inhibitors of pAKT merits further investigation.