2016年12月31日，牛津大学出版社旗下《国家癌症研究所杂志》在线发表休斯顿卫理公会癌症中心、德克萨斯大学MD安德森癌症中心、复旦大学附属肿瘤医院、埃默里大学、康奈尔大学威尔医学院、印第安纳大学医学院的研究报告，开发出一种治疗化生型乳腺癌的潜在疗法，这种乳腺癌是三阴性乳腺癌的恶性亚型，患者的生存不到4年。
化生型乳腺癌在所有乳腺癌类型中占比不到1%，是三阴性乳腺癌的恶性亚型疾病，由于其高度异质性和化学耐药性，至今并无有效疗法对化生型乳腺癌进行治疗，由于这类癌症对化疗具有较高的无应答性，因此患者三年生存率往往低于40%，甚至比三阴性乳腺癌患者70%的生存率还要低，因此确定关键遗传突变对于开发新型疗法治疗这类癌症显得尤为重要。
该研究确定了一种驱动化生型乳腺癌发生的关键基因，不仅揭开了刺激癌症生长的生化通路，还发现了能够阻断该通路的化合物，这就能够有效增加携带人类化生型乳腺肿瘤小鼠的生存。
该研究在化生型乳腺癌患者的40份肿瘤标本中发现39份标本（97.5%）都携带有相同的基因突变：核糖体蛋白L39（RPL39）及其获得性功能突变A14V，该基因类似HER2基因（20%乳腺癌患者的HER2基因过表达），是一种癌基因，这就意味着携带错误基因RPL39的细胞会分裂失控，快速诱发肿瘤产生，而确定RPL39基因仅仅是攻克化生型乳腺癌的第一步。
RPL39基因能够调节诱导型一氧化氮合酶（iNOS）表达，携带较高水平RPL39（风险比：0.71，95%置信区间：0.55～0.91，P=0.006）和iNOS（P=0.003）患者的总生存率往往较低。为此，该研究调查了泛NOS抑制剂NG-甲基-L-精氨酸乙酸酯（L-NMMA）抑制iNOS治疗化生型乳腺癌的效果，结果发现能够减少体外增殖和迁移、BCM-4664和BCM-3807患者来源异种移植模型（P=0.04和P=0.02）、体外和体内化学耐药性。机制上，RPL39通过iNOS信号介导促癌作用，其由RNA编辑酶腺苷脱氨酶驱动，作用于RNA1。
因此，NOS抑制剂和RNA编辑调节剂联合标准化疗可能为化生型乳腺癌提供新的治疗选择，将化生型乳腺癌从顽疾变成临床可控的慢性疾病，目前该研究正在入组患者进行L-NMMA治疗化生型乳腺癌的一期临床研究。
J Natl Cancer Inst. 2016 Dec 31;109(6):djw292.
Role of RPL39 in Metaplastic Breast Cancer.
Dave B, Gonzalez DD, Liu ZB, Li X, Wong H, Granados S, Ezzedine NE, Sieglaff DH, Ensor JE, Miller KD, Radovich M, KarinaEtrovic A, Gross SS, Elemento O, Mills GB, Gilcrease MZ, Chang JC.
Houston Methodist Cancer Center, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Shanghai Cancer Center and Cancer Institute of Fudan University, Shanghai, China; Emory University, Atlanta, GA; Weill Cornell Medical College, New York, NY; Joan and Sanford I. Weill Medical School of Cornell University, New York, NY; Indiana University Medical School, Indianapolis, IN; IU Center for Computational Biology and Bioinformatics, Indianapolis, IN.
BACKGROUND: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer.
METHODS: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39.
RESULTS: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = .006) and iNOS expression (P = .003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor NG-methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = .04 and P = .02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1.
CONCLUSION: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer.
PMID: 28040796
PII: djw292
DOI: 10.1093/jnci/djw292
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