The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries.
The scaffold protein p140Cap limits ERBB2-mediated breast cancer progression interfering with Rac GTPase-controlled circuitries.
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DOI：
10.1038/ncomms14797
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发表时间：
2017-03-16
影响因子：
16.6
通讯作者：
Defilippi P
中科院分区：
文献类型：
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作者：
Grasso S;Chapelle J;Salemme V;Aramu S;Russo I;Vitale N;Verdun di Cantogno L;Dallaglio K;Castellano I;Amici A;Centonze G;Sharma N;Lunardi S;Cabodi S;Cavallo F;Lamolinara A;Stramucci L;Moiso E;Provero P;Albini A;Sapino A;Staaf J;Di Fiore PP;Bertalot G;Pece S;Tosoni D;Confalonieri S;Iezzi M;Di Stefano P;Turco E;Defilippi P
对接蛋白p140Cap负调控肿瘤细胞特征。其对乳腺癌患者生存的相关性，以及其抵消相关癌症信号通路的能力尚未完全了解。我们在此报告，在ERBB2扩增的乳腺癌患者中，p140Cap阳性状态与发生远处事件的概率显著降低相关，并且生存率存在明显差异。p140Cap抑制ERBB2阳性肿瘤细胞进展，损害NeuT小鼠模型中的肿瘤发生和生长，并抵消上皮间质转化，导致转移形成减少。一个主要机制是p140Cap干扰Rac GTP酶控制电路的ERBB 2依赖性激活的能力。我们的研究结果指出p140Cap在抑制ERBB2扩增乳腺癌的侵袭性方面的特定作用，并表明，由于其能够影响特定的分子途径，p140Cap可能代表靶向抗ERBB2治疗反应的预测生物标志物。p140Cap衔接蛋白干扰癌细胞中的粘附和生长因子依赖性信号传导，但机制尚不清楚。在这里，作者表明p140Cap干扰Rac GTP酶控制回路的ERBB2依赖性激活，从而减少转移和癌症进展。
The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival. p140Cap dampens ERBB2-positive tumour cell progression, impairing tumour onset and growth in the NeuT mouse model, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. One major mechanism is the ability of p140Cap to interfere with ERBB2-dependent activation of Rac GTPase-controlled circuitries. Our findings point to a specific role of p140Cap in curbing the aggressiveness of ERBB2-amplified breast cancers and suggest that, due to its ability to impinge on specific molecular pathways, p140Cap may represent a predictive biomarker of response to targeted anti-ERBB2 therapies. p140Cap adaptor proteins interfere with adhesion and growth factor-dependent signalling in cancer cells but the mechanisms are unclear. Here the authors show that p140Cap interferes with ERBB2-dependent activation of Rac GTPase-controlled circuitries reducing metastasis and cancer progression.