Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis
Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis
复制标题
表皮生长因子受体过表达参与促进乳腺癌脑转移
DOI：
10.1002/cncr.27553
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发表时间：
2012-11-01
期刊：
影响因子：
6.2
通讯作者：
Teng, Gao-Jun
中科院分区：
文献类型：
--
作者：
Nie, Fang;Yang, Jian;Teng, Gao-Jun
背景：脑转移性乳腺癌（BMBC）正在增加，由于缺乏有效的治疗方法和潜在的分子机制在很大程度上是未知的，它构成了一个严重的临床问题。最近的研究表明，表皮生长因子受体（EGFR）的失调可能与BMBC的进展有关。然而，EGFR对BMBC的确切作用尚不清楚。方法：通过对人MDA-MB-231乳腺癌细胞（231-BR细胞）的脑营养克隆进行系列分析，探讨EGFR在BMBC中的作用。稳定短发夹RNA转染或激酶抑制剂厄洛替尼可抑制EGFR的表达，肝素结合表皮生长因子样生长因子（HB-EGF）可激活EGFR。体外和体内分析了细胞的生长和侵袭活性。结果：通过粘附实验、伤口愈合实验、Boyden室侵袭实验和细胞骨架染色，EGFR抑制或激活强烈影响231-BR细胞的迁移/侵袭活性。此外，EGFR抑制显著减少231-BR细胞在体内的脑转移。令人惊讶的是，通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）试验、非锚定生长试验和细胞周期分析确定，EGFR表达变化对细胞增殖活性的影响不那么显著。免疫印迹分析表明，EGFR主要通过磷酸肌苷3-激酶/蛋白激酶B和磷脂酶C ？下游通路。此外，由于下游有丝分裂原激活的蛋白激酶途径不敏感，EGFR较少参与增殖。结论：目前的研究结果表明，在231-BR细胞中，EGFR在细胞向脑的迁移和侵袭中发挥的作用比在细胞增殖过程中更重要，为抑制EGFR治疗BMBC的潜在价值提供了新的证据。2012年癌症。(c) 2012年美国癌症协会。
BACKGROUND: Brain-metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear. METHODS: The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells (231-BR cells). EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo. RESULTS: EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay, a wound-healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an anchorage-independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C ? downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway. CONCLUSIONS: The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. (c) 2012 American Cancer Society.