Abstract P4-04-18: Estrogen receptor α-dependent transcriptional induction of selenium-binding protein 1 increases the sensitivity of tamoxifen treatment in breast cancer
Abstract P4-04-18: Estrogen receptor α-dependent transcriptional induction of selenium-binding protein 1 increases the sensitivity of tamoxifen treatment in breast cancer
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摘要 P4-04-18：雌激素受体 α 依赖性硒结合蛋白 1 的转录诱导增加了乳腺癌他莫昔芬治疗的敏感性
DOI：
10.1158/1538-7445.sabcs17-p4-04-18
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发表时间：
2018-02
期刊：
影响因子：
11.2
通讯作者：
Chen Xiaoqing
中科院分区：
文献类型：
--
作者：
Liao Ning;Wang Yulei;Zhang Guochun;Cao Li;Li Kai;Ren Chongyang;Wen Lingzhu;Shi Yumei;Zhu Wenzhen;Chen Xiaoqing
硒结合蛋白1（selenium-binding protein 1，SELENBP 1）的减少在多种实体瘤中经常被观察到，并与不良的临床预后相关，提示SELENBP 1是一种潜在的肿瘤抑制因子。然而，对SELENBP 1转录调控的分子机制仍然知之甚少。本研究首先分析了METABRIC数据集中SELENBP 1 mRNA水平与乳腺癌临床或病理特征的关系，发现SELENBP 1 mRNA水平在PAM 50分子亚型中差异表达，其中Luminal A/B亚型表达水平最高，Basal-like/Claudin-low亚型表达水平最低，表明SELENBP 1可能是雌激素受体α（ERα）的下游参与者。在调整了包括绝经状态、ER/HR/ERBB 2状态、TNM分期和组织学分级在内的临床病理特征后，Kaplan-Meier生存分析意外地显示，在Luminal A亚型中，具有较高水平的SELENBP 1 mRNA（n=43）的患者比具有中等水平的SELENBP 1表达（n=102）的患者具有更短的生存时间（风险比1.59; 95%CI 0.99-2.54;对数秩p=0.0367），尽管具有较低SELENBP 1水平的患者与基底样/紧密连接蛋白低亚型的不良预后一致（风险比1.54; 95%CI 0.97-2.44;对数秩p=0.0356）。为了阐明这一争议，我们使用靶向ERα的shRNA敲低MCF-7细胞中ERα的表达，发现ERα的敲低导致SELENBP 1的mRNA和蛋白表达下调。此外，启动子驱动的荧光素酶报告基因检测结果显示ERα在转录水平上调控了SELENBP 1的表达。有趣的是，我们进一步发现，添加4-羟基他莫昔芬（4-OHT）导致MCF-7细胞中SELENBP 1蛋白表达的显著降低，而MCF-7细胞中SELENBP 1的强制表达显著增强了4-OHT介导的对锚非依赖性癌细胞生长的抑制。总的来说，这些结果表明ERα对SELENBP 1的转录诱导可能在乳腺癌细胞中作为下游肿瘤抑制因子发挥作用，但内分泌治疗由于阻断ERα信号传导而导致SELENBP 1表达下调。Luminal亚型，这可能解释了在管腔型和基底样/紧密连接蛋白低亚型中观察到的SELENBP 1 mRNA水平的差异预测值。我们的实验室正在进行进一步的体外和体内研究，其结果将有助于我们更好地了解SELENBP 1作为改善内分泌治疗疗效的有前途的治疗靶点的临床意义。本研究得到了国家自然科学基金（8160111571）和广东省自然科学基金（2016 A030313768）的部分资助。Citation Format：Liao N，Wang Y，Zhang G，Cao L，Li K，Ren C-Y，Wen L-Z，Shi Y，Zhu W，Chen X.雌激素受体α依赖性硒结合蛋白1转录诱导增加乳腺癌他莫昔芬治疗的敏感性[摘要]。In：Proceedings of the 2017圣安东尼奥Breast Cancer Symposium; 2017 Dec 5-9;圣安东尼奥，TX. Philadelphia（PA）：AACR; Cancer Res 2018;78（4 Suppl）：Abstract nr P4-04-18.
Reduction of selenium-binding protein 1 (SELENBP1) has been frequently observed in various solid tumors, and associated with poor clinical prognosis, implicating SELENBP1 as a potential tumor suppressor. However, the molecular mechanism underlying the transcriptional regulation of SELENBP1 remains poorly understood. In this study, we first analyzed the relationship between SELENBP1 mRNA levels and clinical or pathological features of breast cancer in METABRIC datasets, and found that SELENBP1 mRNA levels were differentially expressed in PAM50 molecular subtypes with highest levels in Luminal A/B subtype and lowest levels in Basal-like/Claudin-low subtype, indicating that SELENBP1 might function as the downstream player of estrogen receptor α (ERα). Following the adjustment of clinicopathological characteristics including the menopausal status, ER/HR/ERBB2 status, TNM stage and histological grade, the Kaplan-Meier survival analysis surprisingly showed that patients with higher levels of SELENBP1 mRNA (n=43) had shorter survival time than those with moderate levels of SELENBP1 expression (n=102) in Luminal A subtype (Hazard Ratio 1.59; 95% CI 0.99-2.54; Logrank p=0.0367), although the patients with lower SELENBP1 levels were consistent the poor prognosis in Basal-like/Claudin-low subtype (Hazard Ratio 1.54; 95% CI 0.97-2.44; Logrank p=0.0356). To elucidate this controversy, we knocked down the expression of ERα in MCF-7 cells using shRNA targeting ERα, and found that knockdown of ERα resulted in the down-regulation of mRNA and protein expression of SELENBP1. In addition, SELENBP1 promoter-driven luciferase reporter assay reveled ERα regulated the expression of SELENBP1 at transcriptional level. Interestingly, we further found that the addition of 4-hydroxytamoxifen (4-OHT) led to a dramatic reduction of SELENBP1 protein expression in MCF-7 cells, while forced expression of SELENBP1 in MCF-7 cells significantly enhanced 4-OHT-mediated inhibition of anchor-independent cancer cell growth. Collectively, these results suggested that the transcriptional induction of SELENBP1 by ERα might function as a downstream tumor suppressor in breast cancer cells, but endocrine therapy led to the down-regulation of SELENBP1 expression due to the blocking of ERα signaling in the patients with Luminal subtype, which was likely to explain the observation of differential predictive value for SELENBP1 mRNA levels in the Luminal and Basal-like/Claudin-low subtypes. Further investigation in vitro and in vivo has been ongoing in our laboratory, and the results from which will help us better understand the clinical relevance for SELENBP1 as a promising therapeutic target in improving the efficacy of endocrine therapy. This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768). Citation Format: Liao N, Wang Y, Zhang G, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Estrogen receptor α-dependent transcriptional induction of selenium-binding protein 1 increases the sensitivity of tamoxifen treatment in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-18.