Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells
Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells
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DOI：
10.1007/s10549-005-9120-9
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发表时间：
2006-06-01
影响因子：
3.8
通讯作者：
Nicholson, Robert I.
中科院分区：
文献类型：
--
作者：
Hiscox, Stephen;Morgan, Liam;Nicholson, Robert I.
SRC激酶在生长因子信号转导中发挥核心作用，调节多种细胞功能，包括增殖、迁移和侵袭。最近的研究表明，在人类肿瘤中，Src活性经常升高，并与疾病的分期有关。我们先前已经证明，在获得三苯氧胺耐药后，MCF7细胞在体外表现出更高的表皮生长因子受体(EGFR)活性和更具侵袭性的表型。由于显示EGFR信号升高的肿瘤可能具有高水平的src活性，我们希望研究src在我们的MCF7内分泌耐药模型中的作用。与野生型MCF7细胞相比，耐他莫昔芬(Tamoxifen)的TAMR细胞中SRC激酶活性显著升高。这一增加不是由于Src蛋白或基因表达增加所致。用新型的Src抑制剂AZD0530处理TAMR细胞，显著减少了两种细胞中可检测到的激活的Src的数量，而对总的Src水平没有影响。AZD0530可显著抑制TAMR细胞的运动性和侵袭性，降低激活的粘着斑激酶(FAK)和帕西林的基础水平，并促进局部粘连的延长。此外，该化合物与EGFR抑制剂吉非替尼联合使用，对抑制TAMR细胞的运动和侵袭有明显的相加作用。这些观察结果表明，在内分泌耐药的乳腺癌细胞中观察到的运动和侵袭表型中，Src起着关键作用。联合使用Src抑制剂和EGFR抑制剂，如吉非替尼，可能会提供一种有效的方法来防止癌症的进展和转移。
Src kinase plays a central role in growth factor signalling, regulating a diverse array of cellular functions including proliferation, migration and invasion. Recent studies have demonstrated that Src activity is frequently elevated in human tumours and correlates with disease stage. We have previously demonstrated that, upon acquisition of tamoxifen resistance, MCF7 cells display increased epidermal growth factor receptor (EGFR) activation and a more aggressive phenotype in vitro. Since tumours exhibiting elevated EGFR signalling may possess elevated levels of Src activity, we wished to investigate the role of Src in our MCF7 model of endocrine resistance. Src kinase activity was significantly elevated in tamoxifen-resistant (TamR) cells in comparison to wild type MCF7 cells. This increase was not due to elevated Src protein or gene expression. Treatment of TamR cells with the novel Src inhibitor, AZD0530, significantly reduced the amount of activated Src detectable in both cell types whilst having no effect on total Src levels. AZD0530 significantly suppressed the motile and invasive nature of TamR cells in vitro, reduced basal levels of activated focal adhesion kinase (FAK) and paxillin and promoted elongation of focal adhesions. Furthermore, the use of this compound in conjunction with the EGFR inhibitor, gefitinib, was markedly additive towards inhibition of TamR cell motility and invasion. These observations suggest that Src plays a pivotal role in mediating the motile and invasive phenotype observed in endocrine-resistant breast cancer cells. The use of Src inhibitors in conjunction with EGFR inhibitors such as gefitinib may provide an effective method with which to prevent cancer progression and metastasis.