Ron Receptor Tyrosine Kinase Activation Confers Resistance to Tamoxifen in Breast Cancer Cell Lines
Ron Receptor Tyrosine Kinase Activation Confers Resistance to Tamoxifen in Breast Cancer Cell Lines
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DOI：
10.1593/neo.10476
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发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Waltz, Susan E.
中科院分区：
文献类型：
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作者：
McClaine, Rebecca J.;Marshall, Aaron M.;Waltz, Susan E.
虽然他莫昔芬治疗与雌激素受体（ER）阳性乳腺肿瘤患者的生存率提高有关，但耐药仍然是一个重要的临床障碍。已证明通过生长因子信号传导途径，特别是通过受体酪氨酸激酶的信号传导以雌二醇非依赖性方式赋予他莫昔芬抗性。罗恩受体酪氨酸激酶是c-Met受体家族的成员，在许多人上皮肿瘤中表达，并且罗恩的表达升高与患有乳腺癌的女性的不良预后相关。在这份报告中，我们评估了罗恩受体激活在人类和小鼠乳腺癌细胞系中对他莫昔芬耐药的作用。罗恩的配体，肝细胞生长因子样蛋白（HGFL）的激活与他莫昔芬诱导的Ron表达细胞系的生长抑制的部分救援。Western分析显示，用他莫昔芬和HGFL处理T47 D人乳腺癌细胞系与丝裂原活化蛋白激酶（MAPK）1/2的磷酸化和ER的丝氨酸残基118的磷酸化增加相关。通过定量逆转录聚合酶链反应，他莫昔芬和HGFL处理的细胞中ER依赖基因的表达增加。所有这些作用都被Ron中和抗体或MEK 1抑制剂抑制，表明作用对罗恩的特异性，以及MAPK 1/2信号通路的参与。总之，这些结果说明了罗恩受体酪氨酸激酶和乳腺癌他莫昔芬耐药的重要机制之间的新联系。Neoplasia（2010）12，650-658
Although tamoxifen treatment is associated with improved survival in patients with estrogen receptor (ER)-positive breast tumors, resistance remains an important clinical obstacle. Signaling through growth factor signaling pathways, in particular through receptor tyrosine kinases, has been demonstrated to confer tamoxifen resistance in an estradiol-independent manner. The Ron receptor tyrosine kinase, a member of the c-Met family of receptors, is expressed in a number of human epithelial tumors, and elevated expression of Ron is associated with poor prognosis in women with breast cancer. In this report, we evaluated the role of Ron receptor activation in conferring resistance to tamoxifen in human and murine breast cancer cell lines. Activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL) was associated with partial rescue from tamoxifen-induced growth inhibition in Ron-expressing cell lines. Western analysis revealed that treatment of the T47D human breast cancer cell line with tamoxifen and HGFL was associated with increased phosphorylation of mitogen-activated protein kinase (MAPK) 1/2 and phosphorylation of serine residue 118 of ER. Expression of ER-dependent genes was increased in cells treated with tamoxifen and HGFL by quantitative reverse transcription-polymerase chain reaction. All of these effects were inhibited by treatment with either a Ron-neutralizing antibody or a MEK1 inhibitor, suggesting the specificity of the effect to Ron, and the involvement of the MAPK 1/2 signaling pathway. In summary, these results illustrate a novel connection between the Ron receptor tyrosine kinase and an important mechanism of tamoxifen resistance in breast cancer. Neoplasia (2010) 12, 650-658