17β-estradiol promotes breast cancer cell proliferation-inducing stromal cell-derived factor-1-mediated epidermal growth factor receptor transactivation:: reversal by gefitinib pretreatment
17β-estradiol promotes breast cancer cell proliferation-inducing stromal cell-derived factor-1-mediated epidermal growth factor receptor transactivation:: reversal by gefitinib pretreatment
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DOI：
10.1124/mol.107.039974
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发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Florio, Tullio
中科院分区：
文献类型：
--
作者：
Pattarozzi, Alessandra;Gatti, Monica;Florio, Tullio
雌激素和表皮生长因子受体（EGFR）家族激动剂的协调活性代表了乳腺癌细胞增殖的主要决定因素。基质细胞衍生因子-1（SDF-1）通过EGFR的反式激活增强细胞外信号调节激酶1和2（ERK 1/2）的活性，17 β-雌二醇（E2）诱导SDF-1产生以发挥自分泌增殖作用。在此基础上，我们评估是否抑制EGFR的酪氨酸激酶（TK）活性可能控制不同的促有丝分裂刺激在乳腺肿瘤中使用EGFR-TK抑制剂吉非替尼拮抗E2诱导的T47 D人乳腺癌细胞的增殖。EGF，E2和SDF-1诱导剂量依赖性T47 D细胞增殖，这是非加性的建议共同的细胞内途径的激活。吉非替尼处理不仅抑制EGF依赖性增殖和ERK 1/2激活，而且抑制SDF-1和E2的作用，表明这些活性是由EGFR反式激活介导的。事实上，SDF-1和E2均引起EGFR酪氨酸磷酸化。E2和SDF-1增殖作用之间的分子联系被确定，因为CXCR 4拮抗剂1，1 '-（1，4-亚苯基双（亚甲基））双-1，4，8，1,1-四氮杂环十四烷八盐酸盐（AMD 3100）抑制SDF-1和E2依赖性增殖以及EGFR和ERK 1/2磷酸化。EGFR反式激活依赖于c-Src激活。E2处理引起T47 D细胞的强大SDF-1释放。最后，在SKBR 3，E2耐药细胞中，EGFR被组成性激活，AMD 3100降低EGFR磷酸化和细胞增殖，而HER 2-neu在SKBR 3中被SDF-1反式激活，但在T47 D细胞中没有。总之，我们发现CXCR 4的激活将增殖信号从E2受体转导至EGFR，EGFR的抑制能够逆转由多受体激活诱导的乳腺癌细胞增殖。
The coordinated activity of estrogens and epidermal growth factor receptor ( EGFR) family agonists represents the main determinant of breast cancer cell proliferation. Stromal cell-derived factor-1 (SDF-1) enhances extracellular signal-regulated kinases 1 and 2 ( ERK1/2) activity via the transactivation of EGFR and 17 beta-estradiol (E2) induces SDF-1 production to exert autocrine proliferative effects. On this basis, we evaluated whether the inhibition of the tyrosine kinase (TK) activity of EGFR may control different mitogenic stimuli in breast tumors using the EGFR-TK inhibitor gefitinib to antagonize the proliferation induced by E2 in T47D human breast cancer cells. EGF, E2, and SDF-1 induced a dose-dependent T47D cell proliferation, that being nonadditive suggested the activation of common intracellular pathways. Gefitinib treatment inhibited not only the EGF-dependent proliferation and ERK1/2 activation but also the effects of SDF-1 and E2, suggesting that these activities were mediated by EGFR transactivation. Indeed, both SDF-1 and E2 caused EGFR tyrosine phosphorylation. The molecular link between E2 and SDF-1 proliferative effects was identified because 1,1'-(1,4- phenylenebis(methylene))bis- 1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist, inhibited SDF-1- and E2-dependent proliferation and EGFR and ERK1/2 phosphorylation. EGFR transactivation was dependent on c-Src activation. E2 treatment caused a powerful SDF-1 release from T47D cells. Finally, in SKBR3, E2-resistant cells, EGFR was constitutively activated, and AMD3100 reduced EGFR phosphorylation and cell proliferation, whereas HER2-neu was transactivated by SDF-1 in SKBR3 but not in T47D cells. In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.