Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.
Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.
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DOI：
10.18632/oncotarget.10787
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发表时间：
2016-08-30
期刊：
影响因子：
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通讯作者：
Moreno-Bueno G
中科院分区：
文献类型：
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作者：
Hergueta-Redondo M;Sarrio D;Molina-Crespo Á;Vicario R;Bernadó-Morales C;Martínez L;Rojo-Sebastián A;Serra-Musach J;Mota A;Martínez-Ramírez Á;Castilla MÁ;González-Martin A;Pernas S;Cano A;Cortes J;Nuciforo PG;Peg V;Palacios J;Pujana MÁ;Arribas J;Moreno-Bueno G
大约 30-40% 的 HER2 阳性乳腺癌并未显示出从靶向治疗中获得的实质性临床益处，因此，耐药性的机制仍然部分未知。有趣的是，ERBB2 经常与可能在这种癌症亚型中发挥相关作用的邻近基因共扩增和共表达。在这里，通过对 2,096 个乳腺肿瘤的数据进行计算机分析，我们揭示了 Gasdermin B (GSDMB) 基因（位于距离 ERBB2 175 kilo碱基远）的表达与 HER2 阳性乳腺癌不良预后的病理和临床参数之间存在显着相关性。接下来，对三个独立队列（总共 286 个肿瘤）的分析表明，大约 65% 的 HER2 阳性病例存在 GSDMB 基因扩增和蛋白过度表达。此外，GSDMB 表达还与新辅助和辅助治疗环境下较低的无复发生存率和病理完全缓解以及阳性淋巴结状态和远处转移的不良治疗反应相关。重要的是，GSDMB 表达可促进不同 HER2 阳性乳腺癌细胞中曲妥珠单抗的存活，并且与患者来源的异种移植物中的体内曲妥珠单抗耐药表型相关。总之，我们的数据确定 ERBB2 共扩增和共表达基因 GSDMB 是 HER2 阳性乳腺癌不良预后和治疗反应的关键决定因素。
Around, 30–40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.