Differential impact of EGFR-targeted therapies on hypoxia responses: implications for treatment sensitivity in triple-negative metastatic breast cancer.
Differential impact of EGFR-targeted therapies on hypoxia responses: implications for treatment sensitivity in triple-negative metastatic breast cancer.
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DOI：
10.1371/journal.pone.0025080
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bignon YJ
中科院分区：
文献类型：
--
作者：
El Guerrab A;Zegrour R;Nemlin CC;Vigier F;Cayre A;Penault-Llorca F;Rossignol F;Bignon YJ
在实体肿瘤中，如乳腺癌，细胞暴露于缺氧中。癌细胞通过激活缺氧诱导因子（hfs）来调节其代谢，hfs促进参与细胞存活、耐药和转移等过程的基因转录。HIF-1也通过激活表皮生长因子受体酪氨酸激酶（EGFR-TK）以不依赖氧的方式被诱导。三阴性乳腺癌（triple negative breast cancer， TNBC）是侵袭性乳腺癌的一种亚型，以激素和HER2受体的阴性表达为特征，该亚型通常过表达EGFR。在转移性TNBC细胞模型（MDA-MB-231）中评估了对三种EGFR抑制剂（西妥昔单抗、吉非替尼和拉帕替尼，一种HER2/EGFR- tk抑制剂）的敏感性，并评估了这些药物对HIF活性和稳定性的影响。对MDA-MB-231细胞进行基因修饰，使其在缺氧诱导下稳定表达增强的绿色荧光蛋白（EGFP）；Ca9-GFP细胞模型报告HIF活性，而GFP-P564报告HIF稳定性。流式细胞术监测报告信号。还评估了HIF-1 dna结合活性、细胞迁移和活力对EGFR抑制剂的反应。在缺氧条件下，细胞荧光信号明显增强（> 30倍）。西妥昔单抗和拉帕替尼不影响缺氧诱导的信号，而吉非替尼在两种细胞模型中均显著降低其强度，并降低MDA-MB-231细胞中HIF-1 α水平和HIF-1 dna结合活性。吉非替尼的这一特性与其抑制MDA-MB-231细胞迁移和以剂量依赖性方式诱导细胞死亡的能力有关。西妥昔单抗和拉帕替尼对细胞迁移和细胞活力没有影响。对西妥昔单抗和拉帕替尼的耐药性以及对吉非替尼的敏感性与它们调节HIF活性和稳定性的能力有关。总之，在TNBC中，通过EGFR信号下调HIF-1似乎是诱导对EGFR靶向治疗的积极反应所必需的。
In solid tumors, such as breast cancer, cells are exposed to hypoxia. Cancer cells adapt their metabolism by activating hypoxia-inducible factors (HIFs) that promote the transcription of genes involved in processes such as cell survival, drug resistance and metastasis. HIF-1 is also induced in an oxygen-independent manner through the activation of epidermal growth factor receptor tyrosine kinase (EGFR-TK). Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer characterized by negative expression of hormonal and HER2 receptors, and this subtype generally overexpresses EGFR. Sensitivity to three EGFR inhibitors (cetuximab, gefitinib and lapatinib, an HER2/EGFR-TK inhibitor) was evaluated in a metastatic TNBC cell model (MDA-MB-231), and the impact of these drugs on the activity and stability of HIF was assessed. MDA-MB-231 cells were genetically modified to stably express an enhanced green fluorescent protein (EGFP) induced by hypoxia; the Ca9-GFP cell model reports HIF activity, whereas GFP-P564 reports HIF stability. The reporter signal was monitored by flow cytometry. HIF-1 DNA-binding activity, cell migration and viability were also evaluated in response to EGFR inhibitors. Cell fluorescence signals strongly increased under hypoxic conditions (> 30-fold). Cetuximab and lapatinib did not affect the signal induced by hypoxia, whereas gefitinib sharply reduced its intensity in both cell models and also diminished HIF-1 alpha levels and HIF-1 DNA-binding activity in MDA-MB-231 cells. This gefitinib feature was associated with its ability to inhibit MDA-MB-231 cell migration and to induce cell mortality in a dose-dependent manner. Cetuximab and lapatinib had no effect on cell migration or cell viability. Resistance to cetuximab and lapatinib and sensitivity to gefitinib were associated with their ability to modulate HIF activity and stability. In conclusion, downregulation of HIF-1 through EGFR signaling seems to be required for the induction of a positive response to EGFR-targeted therapies in TNBC.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
拉帕替尼对转移性乳腺癌细胞生长到大脑的影响。
影响因子：
10.3
作者：
Gril, Brunilde;Palmieri, Diane;Bronder, Julie L.;Herring, Jeanne M.;Vega-Valle, Eleazar;Feigenbaum, Lionel;Liewehr, David J.;Steinberg, Seth M.;Merino, Maria J.;Rubin, Stephen D.;Steeg, Patricia S.
通讯作者：
Steeg, Patricia S.
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
50.5
作者：
Corkery, B.;Crown, J.;O'Donovan, N.
通讯作者：
O'Donovan, N.
影响因子：
11.2
作者：
Pore, N;Jiang, ZB;Maity, A
通讯作者：
Maity, A