Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells.
Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells.
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DOI：
10.3892/ijo.2012.1407
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发表时间：
2012-06
影响因子：
5.2
通讯作者：
D'Assoro AB
中科院分区：
文献类型：
--
作者：
Leontovich AA;Zhang S;Quatraro C;Iankov I;Veroux PF;Gambino MW;Degnim A;McCubrey J;Ingle J;Galanis E;D'Assoro AB
Raf/MEK/MAPK通路的异常激活在乳腺癌的发生和发展中起着关键作用。Raf/MEK/MAPK致癌信号的失调通常由HER-2/Neu酪氨酸激酶受体的过表达引起，导致乳腺癌患者的化学内分泌抵抗、远处转移的发展和最终的不良预后。HER-2/Neu过表达还与上皮向间质转化（EMT）途径的激活、粘附分子的丢失和转移有关。最近，已经证明经历EMT的癌细胞获得CD44 +/CD24 −/低基础癌干细胞样表型，并且特征在于HER-2/Neu和TGF β致癌信号传导通路的激活，具有自我更新、耐药性、侵袭和远处转移的能力增加。转移性播散后，癌细胞通过间质向上皮转化（MET）重新激活某些上皮特性，在继发部位建立肿瘤性病变，尽管调控MET的分子机制仍然难以捉摸。在这项研究中，我们证明Raf-1致癌信号的组成性激活诱导HER-2/Neu过表达，导致ER α + MCF-7乳腺癌异种移植物发生远处转移。重要的是，异种移植模型中远处转移的发生与MET途径的激活有关，其特征在于EMT诱导基因（TGFB2、TWIST 1和FOXC 1）的表达减少以及BMB 7、CXCR 7和EGR家族转录因子的过表达。总之，我们的研究结果首次表明，在肿瘤生长过程中Raf/MEK/MAPK致癌信号的扩增通过激活间充质上皮转化促进原发性肿瘤转移性病变的发生。
Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis. Recently, it has been demonstrated that cancer cells that undergo EMT acquire a CD44+/CD24−/low basal cancer stem cell-like phenotype and are characterized by activation of HER-2/Neu and TGFβ oncogenic signaling pathways with increased capacity of self-renewal, drug resistance, invasion and distant metastases. Following meta-static dissemination, cancer cells re-activate certain epithelial properties through mesenchymal to epithelial transition (MET) to establish neoplastic lesions at secondary sites, although the molecular mechanisms regulating MET remain elusive. In this study we demonstrate that constitutive activation of Raf-1 oncogenic signaling induces HER-2/Neu overexpression leading to the development of distant metastases in ERα+ MCF-7 breast cancer xenografts. Importantly, development of distant metastases in xenograft models was linked to activation of the MET pathway characterized by reduced expression of EMT inducer genes (TGFB2, TWIST1 and FOXC1) and overexpression of BMB7, CXCR7 and EGR family of transcription factors. In summary, our results demonstrate for the first time that amplification of Raf/MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition.
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影响因子：
3.6
作者：
Freudenberg, Jaclyn A.;Wang, Qiang;Katsumata, Makoto;Drebin, Jeffrey;Nagatomo, Izumi;Greene, Mark I.
通讯作者：
Greene, Mark I.
CD44同工型在乳腺癌中异质表达，并与肿瘤亚型和癌症干细胞标记相关。
影响因子：
3.8
作者：
Olsson E;Honeth G;Bendahl PO;Saal LH;Gruvberger-Saal S;Ringnér M;Vallon-Christersson J;Jönsson G;Holm K;Lövgren K;Fernö M;Grabau D;Borg A;Hegardt C
通讯作者：
Hegardt C
影响因子：
6.4
作者：
Ghayad, Sandra E.;Vendrell, Julie A.;Cohen, Pascale A.
通讯作者：
Cohen, Pascale A.
影响因子：
3.5
作者：
Bartlett, Alastair I.;Starcyznski, Jane;Bartlett, John M. S.
通讯作者：
Bartlett, John M. S.
影响因子：
2.4
作者：
Al-azawi, Dhafir;Leong, Sum;Young, Leonie
通讯作者：
Young, Leonie