Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.
Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.
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DOI：
10.18632/oncotarget.2846
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Lakhani SR
中科院分区：
文献类型：
--
作者：
Momeny M;Saunus JM;Marturana F;McCart Reed AE;Black D;Sala G;Iacobelli S;Holland JD;Yu D;Da Silva L;Simpson PT;Khanna KK;Chenevix-Trench G;Lakhani SR
HER2阳性的乳腺肿瘤与脑部复发的高风险有关。HER3被认为是HER2(由ERBB2编码)不可或缺的信号底物，在乳腺癌脑转移中被诱导，尽管这种致癌二聚体促进脑转移的分子机制仍然不清楚。我们研究了HER3-HER2的配体hereglin(在大脑中广泛表达)对体外培养的乳腺癌细胞株的影响。SKBr3(ERBB2扩增)、MDA-MB-361(ERBB2扩增，脑转移瘤来源)和MCF7(HER2阳性，非ERBB2扩增)细胞用外源性Hereglin处理后，细胞增殖和黏附能力增强，同时诱导细胞周期蛋白D1和ICAM-1，抑制p27。在Transwell实验中，所有三种细胞系都通过Matrigel向Hereglin趋化信号侵袭，与细胞外组织蛋白酶B和基质金属蛋白酶-9(MMP-9)的激活有关。此外，Hereglin诱导乳腺癌细胞跨越原代人脑微血管内皮细胞的紧密屏障迁移。这依赖于HER2、HER3和MMPs的活性，并通过使用Herceptin®和人源化HER3单抗EV20联合阻断HER2-HER3而完全被取消。总而言之，这些数据提示HER3-HER2二聚体在富含HER3-HER2的脑微环境中促进转移性肿瘤发展的机制。
HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.
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MMP及其抑制剂在乳腺癌肿瘤组织标本中的抑制剂与具有不同转移潜能的细胞系中的相关性。
影响因子：
3.8
作者：
Figueira RC;Gomes LR;Neto JS;Silva FC;Silva ID;Sogayar MC
通讯作者：
Sogayar MC
影响因子：
3.8
作者：
Kim J;Jeong H;Lee Y;Kim C;Kim H;Kim A
通讯作者：
Kim A
影响因子：
3.9
作者：
Berghoff, Anna S.;Bartsch, Rupert;Birner, Peter
通讯作者：
Birner, Peter
DOI：
10.1038/nrclinonc.2011.58
发表时间：
2011-06
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.5
作者：
Eceles, SA
通讯作者：
Eceles, SA