Guo Zhaorong, Tada Hiroshi, Kitamura Narufumi, Hamada Yoh, Miyashita Minoru, Harada-Shoji Narumi, Sato Akiko, Hamanaka Yohei, Tsuboi Kouki, Harada Nobuhisa, Takano-Kasuya Mayumi, Okada Hisatake, Nakano Yasushi, Ohuchi Noriaki, Hayashi Shin-Ichi, Ishida Takanori, Gonda Kohsuke
Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.
Cancers (Basel). 2019 Apr 12;11(4):526. doi: 10.3390/cancers11040526.
In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed "the nearest-neighbor method" to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quantification of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR ( = 0.94) and flow cytometry ( = 0.98). High ERα ENR was significantly associated with poor overall survival ( = 0.048) and disease-free survival (DFS) ( = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4-11.8; = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR/HER2 BC indicates decreased likelihood of benefiting from ET.
除基因组信号传导外，雌激素受体α（ERα）还通过促进内分泌治疗（ET）耐药的核外信号传导与细胞增殖和存活相关。然而，核外ERα与ET耐药之间的关系尚未得到广泛研究。我们试图通过使用磷整合点免疫组织化学（IHC-PIDs）来测量核外ERα表达，并评估其对ET耐药的预测价值。在体外通过IHC-PIDs对ERα进行定量检测后，我们开发了“最近邻法”来计算核外ERα。此外，我们通过IHC-PIDs检查了65例HR+/HER2-乳腺癌患者的组织切片，并使用该新方法测量了总ERα、核ERα、核外ERα PIDs评分以及核外与核内ERα的比率（ENR）。我们证明，使用IHC-PIDs对ERα进行定量与实时qRT-PCR（r = 0.94）和流式细胞术（r = 0.98）具有很强的相关性。高ERα ENR与较差的总生存期（r = 0.048）和无病生存期（DFS）（r = 0.007）显著相关。多变量分析显示，ERα ENR是DFS的独立预后因素[风险比，3.8；95% CI，1.4 - 11.8；P = 0.006]。我们的自动测量在定位和评估核外ERα方面具有很高的准确性。HR+/HER2-乳腺癌中高ERα ENR表明从ET中获益的可能性降低。
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