CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer.
CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer.
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DOI：
10.1007/s10549-015-3458-4
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发表时间：
2015-07
影响因子：
3.8
通讯作者：
Parise LV
中科院分区：
文献类型：
--
作者：
Black JL;Harrell JC;Leisner TM;Fellmeth MJ;George SD;Reinhold D;Baker NM;Jones CD;Der CJ;Perou CM;Parise LV
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，预后通常较差，并且没有可用的靶向治疗，这凸显了识别和表征新治疗靶点的关键未得到满足的需求。我们之前证明 CIB1 通过调节两条致癌信号通路 RAF-MEK-ERK 和 PI3K-AKT 对于癌细胞存活和增殖是必需的。由于这些通路在 TNBC 中经常上调，因此我们假设 CIB1 可能在 TNBC 细胞存活和肿瘤生长中发挥更广泛的作用。使用的方法包括体外和体内 CIB1 的诱导性 RNAi 耗竭、免疫印迹、克隆形成测定、流式细胞术、RNA 测序、生物信息学分析和 Kaplan-Meier 生存分析。在测试的 11 个 TNBC 细胞系中，CIB1 缺失导致 8 个细胞显着死亡。对 PI3K-AKT 和 RAF-MEK-ERK 信号传导相关成分的分析表明，AKT 激活状态升高和 PTEN 表达低是 CIB1 耗竭敏感性的关键预测因子。此外，CIB1 敲低导致体内 MDA-MB-468 异种移植肿瘤急剧缩小。 RNA序列分析还表明，TNBC细胞中CIB1的缺失会激活与增殖减少和细胞死亡增加相关的基因程序。 CIB1 表达水平本身并不能预测 TNBC 对 CIB1 缺失的易感性，并且 CIB1 mRNA 表达水平与 TNBC 患者的生存率无关。我们的数据与新兴的非癌基因成瘾理论一致，其中很大一部分 TNBC 依赖 CIB1 来维持细胞存活和肿瘤生长，而与 CIB1 表达水平无关。我们的数据表明 CIB1 是 TNBC 的新治疗靶点。
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with generally poor prognosis and no available targeted therapies, highlighting a critical unmet need to identify and characterize novel therapeutic targets. We previously demonstrated that CIB1 is necessary for cancer cell survival and proliferation via regulation of two oncogenic signaling pathways, RAF–MEK–ERK and PI3K–AKT. Because these pathways are often upregulated in TNBC, we hypothesized that CIB1 may play a broader role in TNBC cell survival and tumor growth. Methods utilized include inducible RNAi depletion of CIB1 in vitro and in vivo, immunoblotting, clonogenic assay, flow cytometry, RNA-sequencing, bioinformatics analysis, and Kaplan–Meier survival analysis. CIB1 depletion resulted in significant cell death in 8 of 11 TNBC cell lines tested. Analysis of components related to PI3K–AKT and RAF–MEK–ERK signaling revealed that elevated AKT activation status and low PTEN expression were key predictors of sensitivity to CIB1 depletion. Furthermore, CIB1 knockdown caused dramatic shrinkage of MDA-MB-468 xenograft tumors in vivo. RNA sequence analysis also showed that CIB1 depletion in TNBC cells activates gene programs associated with decreased proliferation and increased cell death. CIB1 expression levels per se did not predict TNBC susceptibility to CIB1 depletion, and CIB1 mRNA expression levels did not associate with TNBC patient survival. Our data are consistent with the emerging theory of non-oncogene addiction, where a large subset of TNBCs depend on CIB1 for cell survival and tumor growth, independent of CIB1 expression levels. Our data establish CIB1 as a novel therapeutic target for TNBC.