Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer
Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer
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DOI：
10.1093/jnci/djx207
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发表时间：
2018-04-01
影响因子：
10.3
通讯作者：
Kong, Gu
中科院分区：
文献类型：
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作者：
Choi, Hee-Joo;Joo, Hyeong-Seok;Kong, Gu
背景：尽管内分泌治疗有好处，但治疗期间或治疗后获得性耐药仍然是雌激素受体（ER）阳性乳腺癌的主要挑战。我们研究了组蛋白去甲基酶视网膜母细胞瘤结合蛋白 2 (RBP2) 在乳腺癌内分泌治疗耐药中的潜在作用。方法：根据 RBP2 表达，在三个不同的乳腺癌队列中分析乳腺癌患者的生存情况，包括 METABRIC (n = 1980) 和 KM Plotter (n = 1764)。 RBP2 介导的他莫昔芬耐药性通过体外磺罗丹明 B (SRB) 比色、集落形成测定和体内异种移植模型（每组 n = 8）得到证实。通过 RNA-seq 分析和受体酪氨酸激酶测定来鉴定 RBP2 对他莫昔芬的耐药机制。所有统计检验都是双向的。结果：RBP2 与 ER 阳性乳腺癌中他莫昔芬治疗的不良预后相关（HYU 队列中 P = 0.04，KM 绘图仪中 P = 0.02，METABRIC 中 P = 0.007，时序检验）。此外，对他莫昔芬耐药的乳腺癌患者中 RBP2 表达升高（P = 0.04，卡方检验）。 RBP2 的敲除赋予他莫昔芬敏感性，而 RBP2 的过表达在体外和体内诱导他莫昔芬耐药性（MCF7 异种移植物：他莫昔芬治疗的对照，平均 [SD] 肿瘤体积 = 70.8 [27.9] mm(3)，与他莫昔芬治疗的 RBP2 相比，平均 [SD] 肿瘤体积 = 387.9 [85.1] mm(3)，P < .001）。从机制上讲，RBP2 与 ER 共激活因子和辅抑制因子合作，调节多个他莫昔芬耐药相关基因，包括 NRIP1、CCND1、IGFBP4 和 IGFBP5。此外，RBP2-ER-NRIP1-HDAC1 复合物对 IGFBP4/5 的表观遗传沉默导致胰岛素样生长因子 1 受体 (IGF1R) 激活。 RBP2 还通过去甲基酶活性独立的 ErbB 蛋白稳定作用增加了 IGF1R-ErbB 串扰和随后的 PI3K-AKT 激活。他莫昔芬和 PI3K 抑制剂联合治疗可以克服 RBP2 介导的他莫昔芬耐药性（RBP2 过表达细胞：细胞活力百分比 [SD]，他莫昔芬 = 89.0 [3.8]%，与他莫昔芬加 BKM120 = 41.3 [5.6]%，P < .001）。结论：RBP2 激活ER-IGF1R-ErbB 信号级联以多种方式诱导他莫昔芬耐药，表明 RBP2 是 ER 驱动的癌症的潜在治疗靶点。
Background: Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer.Methods: Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by in vitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and in vivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided.Results: RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance in vitro and in vivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm(3), vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm(3), P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1- HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen resistance (RBP2-overexpressing cells: % cell viability [SD], tamoxifen = 89.0 [3.8]%, vs tamoxifen with BKM120 = 41.3 [5.6]%, P < .001).Conclusions: RBP2 activates ER-IGF1R-ErbB signaling cascade in multiple ways to induce tamoxifen resistance, suggesting that RBP2 is a potential therapeutic target for ER-driven cancer.