p130Cas is an essential transducer element in ErbB2 transformation
p130Cas is an essential transducer element in ErbB2 transformation
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DOI：
10.1096/fj.10-157347
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Defilippi, Paola
中科院分区：
文献类型：
--
作者：
Cabodi, Sara;Tinnirello, Agata;Defilippi, Paola
ErbB2癌基因常在乳腺肿瘤中过度表达，并与不良临床预后相关。p130Cas是一种在正常和病理细胞中调节细胞存活、迁移和增殖的节点支架蛋白。p130Cas在ErbB2依赖性乳腺肿瘤发生中的功能作用是通过其在来自过表达ErbB2的小鼠乳腺肿瘤（N202-1A细胞）的乳腺癌细胞中的沉默，以及在ErbB2转化的p130Cas缺失的小鼠胚胎成纤维细胞中的重新表达来评估的。我们证明p130Cas是erbb2依赖性病灶形成、锚定非依赖性生长和原位N202-1A肿瘤体内生长所必需的。此外，在Balbc-NeuT小鼠乳腺中乳头内注射p130cas稳定的sirna可降低自发性肿瘤的生长。在ErbB2转化的细胞中，p130Cas是ErbB2、c-Src和Fak组成的功能性分子复合物的关键成分。在人乳腺细胞中，MCF10A。B2，伴随ErbB2的激活和p130Cas的过表达维持和加强信号传导，导致Rac1激活和MMP9分泌，从而具有侵袭性。一致地，p130Cas驱动N202-1A细胞在体内的肺转移定植。这些结果表明p130Cas是ErbB2转化的重要换能器，并突出了其作为ErbB2阳性人类乳腺癌的新治疗靶点的潜力。-Cabodi， S., Tinnirello， A., Bisaro， B., Tornillo， G., camaco - leal, m.p ., Forni， G., Cojoca， R., Iezzi， M., Amici， A., Montani， M., Eva， A., Di Stefano， P., Muthuswamy, s.k, Tarone， G., Turco， E., Defilippi， P. p130Cas是ErbB2转化过程中必不可少的传感器元件。中国生物医学工程学报，2009,32(4):481 - 481。www.fasebj.org
The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A. B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation. FASEB J. 24, 3796-3808 (2010). www.fasebj.org