The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis.
The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis.
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DOI：
10.1111/j.1600-0854.2009.00917.x
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Onodera Y
中科院分区：
文献类型：
--
作者：
Sabe H;Hashimoto S;Morishige M;Ogawa E;Hashimoto A;Nam JM;Miura K;Yano H;Onodera Y
肿瘤是组织特异性疾病，其侵袭和转移机制具有高度多样性。在乳腺癌中，与侵袭性表型特异性相关的生物标志物尚未明确确定。一个小的 GTPase Arf6 主要调节质膜成分的回收。我们发现Arf6及其效应子AMAP1（DDEF1、DEF1、ASAP1和centaurin β4）在一些乳腺癌中异常过度表达，并用于乳腺癌的侵袭和转移。这些蛋白质的过度表达与其基因的转录上调无关，并且仅发生在高度恶性的乳腺癌细胞中。我们最近发现 GEP100 (BRAG2) 通过直接与配体激活的表皮生长因子受体 (EGFR) 结合，负责 Arf6 激活，从而诱导侵袭和转移。我们的一系列研究表明，EGFR侵袭通路的激活需要Arf6和AMAP1均高度过表达，且EGFR被配体激活。病理分析表明，大量人类导管癌可能利用 EGFR-GEP100-Arf6-AMAP1 通路来治疗其恶性肿瘤。微环境与乳腺肿瘤的恶性程度密切相关。我们的结果揭示了一些乳腺癌精确分子机制的一个方面，其中完全侵袭性不仅仅通过癌细胞的细胞内改变获得，而且来自微环境的细胞外因素也可能是必要的。还将讨论将我们的知识转化为癌症治疗的可能性。
Tumors are tissue-specific diseases, and their mechanisms of invasion and metastasis are highly diverse. In breast cancer, biomarkers that specifically correlate with the invasive phenotypes have not been clearly identified. A small GTPase Arf6 primarily regulates recycling of plasma membrane components. We have shown that Arf6 and its effector AMAP1 (DDEF1, DEF1, ASAP1 and centaurin β4) are abnormally overexpressed in some breast cancers and used for their invasion and metastasis. Overexpression of these proteins is independent of the transcriptional upregulation of their genes, and occurs only in highly malignant breast cancer cells. We recently identified GEP100 (BRAG2) to be responsible for the Arf6 activation to induce invasion and metastasis, by directly binding to ligand-activated epidermal growth factor receptor (EGFR). A series of our studies revealed that for activation of the invasion pathway of EGFR, it is prerequisite that Arf6 and AMAP1 both are highly overexpressed, and that EGFR is activated by ligands. Pathological analyses indicate that a significant large population of human ductal cancers may utilize the EGFR-GEP100-Arf6-AMAP1 pathway for their malignancy. Microenvironments have been highly implicated in the malignancy of mammary tumors. Our results reveal an aspect of the precise molecular mechanisms of some breast cancers, in which full invasiveness is not acquired just by intracellular alterations of cancer cells, but extracellular factors from microenvironments may also be necessary. Possible translation of our knowledge to cancer therapeutics will also be discussed.
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