Gefitinib prevents cancer progression in mice expressing the activated rat HER2/neu
Gefitinib prevents cancer progression in mice expressing the activated rat HER2/neu
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DOI：
10.1002/ijc.23231
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发表时间：
2008-04-15
影响因子：
6.4
通讯作者：
Yoo, George H.
中科院分区：
文献类型：
--
作者：
Piechocki, Marie P.;Dibbley, Susan K.;Yoo, George H.
我们在BALB-NeuT转基因小鼠中测试了吉非替尼在预防HER 2/neu介导的乳腺癌发展中的功效。对5 - 14周龄的雌性转基因小鼠口服吉非替尼可将肿瘤多样性从9.6 +/- 0.82降至0.58 +/- 1.1（83%）。我们观察到治疗小鼠的小叶和小叶结节的数量和大小减少，每个腺体的总体疾病负担减少。吉非替尼不影响乳腺导管的正常发育。这些动物的腮腺腺泡细胞癌的发展也减少了，同时在进展过程中间质受累减少。吉非替尼消除了小叶增生和癌中HER 2和HER 3的磷酸化以及通过MAPK和Akt的信号传导。与此同时，吉非替尼处理的动物脾细胞和淋巴结中的MAPK活性和细胞因子产生增加，与淋巴结大小增加一致。延迟吉非替尼治疗直至乳腺出现非典型小叶增生，会降低疗效。这些研究证明了HER 2信号转导在HER 2/neu依赖性乳腺癌的发生和进展中的关键作用，并表明特异性抑制剂在预防早期增生性疾病的生长中的作用。(c)2007 Wiley-Liss，Inc.
We tested the efficacy of gefitinib in the prevention of HER2/neu-mediated breast cancer development in BALB-NeuT transgenic mice. Oral administration of gefitinib to female transgenic mice from 5 to 14 weeks of age reduced tumor multiplicity from 9.6 +/- 0.82 to 0.58 +/- 1.1 (83%). We observed a decrease in the number and size of lobules and lobular nodules in treated mice with a reduction in the overall disease burden per gland. Normal duct development in the mammary glands was not affected by gefitinib. The development of acinic cell carcinoma in the parotid glands of these animals was also reduced coincident with decreased stromal involvement during progression. Gefitinib eliminated phosphorylation of HER2 and HER3 and signaling through MAPK and Akt in lobular hyperplasias and carcinomas. At the same time MAPK activity and cytokine production in splenocytes and lymph nodes was increased in gefitinib-treated animals coincident with an increase in lymph node size. Delaying gefitinib treatment until mammary glands exhibited atypical lobular hyperplasias reduced efficacy. These studies demonstrate the critical role of HER2 signal transduction in the onset and progression of HER2/neu-dependent breast cancer and suggest a role for specific inhibitors to prevent the outgrowth of early hyperplastic disease. (c) 2007 Wiley-Liss, Inc.