Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis
Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis
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DOI：
10.1038/ng1963
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发表时间：
2007-03-01
期刊：
影响因子：
30.8
通讯作者：
Tremblay, Michel L.
中科院分区：
文献类型：
--
作者：
Julien, Sofi G.;Dube, Nadia;Tremblay, Michel L.
我们使用遗传和药理学方法研究了蛋白酪氨酸磷酸酶 1B (PTP1B) 在乳腺肿瘤发生中的作用。先前已表明，编码其胞外结构域的 Erbb2 区域具有缺失突变的转基因小鼠（称为 NDL2 小鼠，即“胞外结构域 2 中的 Neu 缺失”）会发展为进展为肺转移的乳腺肿瘤。然而，通过与 Ptpn1 缺陷小鼠繁殖或用特定 PTP1B 抑制剂治疗来删除 NDL2 转基因小鼠中的 PTP1B 活性，会导致显着的乳腺肿瘤潜伏期和对肺转移的抵抗力。相反，乳腺中 PTP1B 的特异性过度表达会导致自发性乳腺癌的发生。 PTB1B 对 ErbB2 诱导的乳腺肿瘤发生的调节是通过减弱 MAP 激酶 (MAPK) 和 Akt 途径来实现的。该报告为 PTP1B 作为乳腺癌新治疗靶点的开发提供了理论基础。
We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer.