RB1 deficiency in triple-negative breast cancer induces rnitochondrial protein translation
RB1 deficiency in triple-negative breast cancer induces rnitochondrial protein translation
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DOI：
10.1172/jci81568
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发表时间：
2016-10-01
影响因子：
15.9
通讯作者：
Zacksenhaus, Eldad
中科院分区：
文献类型：
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作者：
Jones, Robert A.;Robinson, Tyler J.;Zacksenhaus, Eldad
三阴性乳腺癌（TNBC）包括基底样和低紧密连接蛋白亚型，目前尚无特异性治疗方法。尽管在三阴性乳腺癌中，视网膜母细胞瘤肿瘤抑制基因（RB1）常常与TP53一起缺失，但它不能直接作为治疗靶点。因此，人们对确定RB1下游可用于治疗的脆弱靶点非常感兴趣。在此，我们确定在多种乳腺上皮细胞中，小鼠Rb和p53的联合失活诱导出具有Met、Birc2/3 - Mmp13 - Yap1和Pvt1 - Myc扩增的低紧密连接蛋白样三阴性乳腺癌。基因集富集分析显示，与仅缺失p53的肿瘤相比，Rb/p53缺失的肿瘤中线粒体蛋白质翻译（MPT）基因通路的表达升高。相应地，生物信息学、功能和生化分析表明，RB1 - E2F复合物与MPT基因启动子结合以调节转录并控制MPT。此外，对美国食品药品监督管理局（FDA）批准的药物进行筛选，确定MPT拮抗剂替加环素（TIG）是一种对Rb/p53缺失的肿瘤细胞增殖有强效抑制作用的药物。TIG优先抑制RB1缺失的三阴性乳腺癌细胞增殖，对肿瘤主体细胞和癌症干细胞部分均有作用，并强烈抑制异种移植物的生长。在细胞培养和异种移植物实验中，它还与柳氮磺胺吡啶（一种FDA批准的胱氨酸xCT反向转运体抑制剂）协同作用。我们的研究结果表明，RB1缺失部分通过增强线粒体功能促进癌细胞增殖，并确定TIG是一种可用于RB1缺失的三阴性乳腺癌的临床批准药物。
Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration-approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.