Crk adaptor proteins act as key signaling integrators for breast tumorigenesis.
Crk adaptor proteins act as key signaling integrators for breast tumorigenesis.
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DOI：
10.1186/bcr3183
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发表时间：
2012-05-08
期刊：
影响因子：
--
通讯作者：
Park M
中科院分区：
文献类型：
--
作者：
Fathers KE;Bell ES;Rajadurai CV;Cory S;Zhao H;Mourskaia A;Zuo D;Madore J;Monast A;Mes-Masson AM;Grosset AA;Gaboury L;Hallet M;Siegel P;Park M
CT10激酶（Crk）适配蛋白（CrkI， CrkII和CrkL）在高度恶性乳腺癌细胞系迁移和侵袭的信号整合中发挥作用。这具有重要意义，因为在一小群乳腺癌患者中观察到CrkI/II蛋白水平升高，这确定了Crk蛋白在乳腺癌进展中的潜在作用。许多体外研究确定了Crk蛋白在细胞运动中的作用，但对于Crk蛋白如何促进乳腺癌在体内的进展知之甚少。通过使用CrkII过表达后产生的基因表达特征分析已发表的乳腺癌数据集，并通过检测乳腺肿瘤组织微阵列中的Crk蛋白表达，评估Crk蛋白在人类乳腺癌中的临床意义（n = 254）。在两种基底乳腺癌细胞系MDA-231 1833TR和SUM1315中，使用短发夹RNA （shRNA）介导的方法实现了Crk （CrkI/CrkII/CrkL）蛋白的稳定敲低，其中前者具有形成骨转移的高亲和力。通过体外实验（细胞迁移、侵袭、软琼脂生长）和体内实验（心脏、胫骨和乳腺脂肪垫注射）来评估Crk蛋白在乳腺癌中的功能意义。CrkII过表达后产生的基因特征与基础乳腺癌以及一般的高分级和不良预后显著相关。此外，组织微阵列上升高的Crk免疫染色显示与基底亚型的高增殖肿瘤有显著关联。在转移性基底乳腺癌细胞中，rnai介导的三种Crk蛋白的敲低表明，Crk在体外的细胞迁移和侵袭以及体内的转移生长中都是持续需要的。此外，Crk消融抑制非锚定生长和体内原位肿瘤生长。这与细胞增殖减少有关，并通过非shrna靶向CrkI/II的表达得以挽救。肿瘤进展中的扰动与整合素信号的改变相关，包括细胞扩散减少、p130Cas磷酸化减少和Cdc42激活。这些数据强调了Crk蛋白在调节侵袭性基底乳腺癌细胞生长中的生理重要性，并确定了Crk依赖的信号网络是有希望的治疗靶点。
CT10 regulator of kinase (Crk) adaptor proteins (CrkI, CrkII and CrkL) play a role in integrating signals for migration and invasion of highly malignant breast cancer cell lines. This has important implications, as elevated CrkI/II protein levels were observed in a small cohort of breast cancer patients, which identified a potential role for Crk proteins in breast cancer progression. Numerous in vitro studies identified a role for Crk proteins in cell motility, but little is known about how Crk proteins contribute to breast cancer progression in vivo. The clinical significance of Crk proteins in human breast cancer was assessed by analyzing published breast cancer datasets using a gene expression signature that was generated following CrkII over-expression and by examining Crk protein expression in tissue microarrays of breast tumors (n = 254). Stable knockdown of Crk (CrkI/CrkII/CrkL) proteins was accomplished using a short hairpin RNA (shRNA)-mediated approach in two basal breast cancer cell lines, MDA-231 1833TR and SUM1315, where the former have a high affinity to form bone metastases. Both in vitro assays (cell migration, invasion, soft agar growth) and in vivo experiments (intra-cardiac, tibial and mammary fat pad injections) were performed to assess the functional significance of Crk proteins in breast cancer. A gene signature derived following CrkII over-expression correlated significantly with basal breast cancers and with high grade and poor outcome in general. Moreover, elevated Crk immunostaining on tissue microarrays revealed a significant association with highly proliferative tumors within the basal subtype. RNAi-mediated knockdown of all three Crk proteins in metastatic basal breast cancer cells established a continued requirement for Crk in cell migration and invasion in vitro and metastatic growth in vivo. Furthermore, Crk ablation suppressed anchorage independent growth and in vivo orthotopic tumor growth. This was associated with diminished cell proliferation and was rescued by expression of non-shRNA targeted CrkI/II. Perturbations in tumor progression correlated with altered integrin signaling, including decreased cell spreading, diminished p130Cas phosphorylation, and Cdc42 activation. These data highlight the physiological importance of Crk proteins in regulating growth of aggressive basal breast cancer cells and identify Crk-dependent signaling networks as promising therapeutic targets.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.8
作者：
MAYER, BJ;HAMAGUCHI, M;HANAFUSA, H
通讯作者：
HANAFUSA, H
影响因子：
50.3
作者：
Kang, YB;Siegel, PM;Massagué, J
通讯作者：
Massagué, J
影响因子：
8
作者：
Mak, H. H. L.;Peschard, P.;Park, M.
通讯作者：
Park, M.