ErbB公司
曲妥珠单抗
癌症研究
生物
车站3
细胞周期蛋白D1
乳腺癌
STAT蛋白
信号转导
癌症
细胞生物学
细胞周期
遗传学
作者
Rosalía Cordo Russo,Wendy Béguelin,María Celeste Díaz Flaqué,Cecilia J. Proietti,Leandro Venturutti,Natalia M. Galigniana,Mercedes Tkach,Pablo Guzmán,Juan Carlos Roa,Neil A. O’Brien,Eduardo H. Charreau,Roxana Schillaci,Patricia V. Elizalde
出处
期刊:Oncogene
[Springer Nature]
日期:2014-09-01
卷期号:34 (26): 3413-3428
被引量:43
摘要
Membrane overexpression of ErbB-2/HER2 receptor tyrosine kinase (membrane ErbB-2 (MErbB-2)) has a critical role in breast cancer (BC). We and others have also shown the role of nuclear ErbB-2 (NErbB-2) in BC, whose presence we identified as a poor prognostic factor in MErbB-2-positive tumors. Current anti-ErbB-2 therapies, as with the antibody trastuzumab (Ttzm), target only MErbB-2. Here, we found that blockade of NErbB-2 action abrogates growth of BC cells, sensitive and resistant to Ttzm, in a scenario in which ErbB-2, ErbB-3 and Akt are phosphorylated, and ErbB-2/ErbB-3 dimers are formed. Also, inhibition of NErbB-2 presence suppresses growth of a preclinical BC model resistant to Ttzm. We showed that at the cyclin D1 promoter, ErbB-2 assembles a transcriptional complex with Stat3 (signal transducer and activator of transcription 3) and ErbB-3, another member of the ErbB family, which reveals the first nuclear function of ErbB-2/ErbB-3 dimer. We identified NErbB-2 as the major proliferation driver in Ttzm-resistant BC, and demonstrated that Ttzm inability to disrupt the Stat3/ErbB-2/ErbB-3 complex underlies its failure to inhibit growth. Furthermore, our results in the clinic revealed that nuclear interaction between ErbB-2 and Stat3 correlates with poor overall survival in primary breast tumors. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight NErbB-2 as a novel target to overcome Ttzm resistance.
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