Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer
Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer
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DOI：
10.1158/0008-5472.can-06-4610
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Neel, Benjamin G.
中科院分区：
文献类型：
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作者：
Bentires-Alj, Mohamed;Neel, Benjamin G.
蛋白酪氨酸磷酸酶 1B（PTP1B；PTPN1）是哺乳动物新陈代谢的重要调节因子，还有助于控制生长因子、细胞因子和细胞外基质的信号传导。小鼠基因敲除研究证实 PTP1B 是胰岛素和瘦素受体的关键负调节因子。使用 PTP1B(-/-) 成纤维细胞系、显性失活突变体或小干扰 RNA 进行的实验表明，PTP1B 也有助于表皮生长因子受体和血小板衍生生长因子受体的去磷酸化。然而，PTP1B 也可能在某些生长因子受体和整合素的下游发挥一些积极（信号增强）作用。先前的研究表明，PTP1B 在乳腺癌和卵巢癌的重要子集中过度表达，尤其是在过度表达 HER2/Neu（HER2(+) 肿瘤）的肿瘤中。然而，使用组织培养细胞进行的实验对于 PTP1B 在 HER2 信号传导中的影响产生了相互矛盾的结果，使得 PTP1B 过度表达对乳腺癌发生的影响尚不清楚。为了确定 PTP1B 缺陷如何影响 HER2 诱发的乳腺肿瘤发生，我们培育了缺乏 PTP1B 一个或两个等位基因的小鼠乳腺肿瘤病毒 (MMTV)-NeuNT 转基因小鼠。尽管 PTP1B 杂合缺失对肿瘤发生没有影响，但 PTP1B 纯合缺陷可显着延迟或阻止 MMTV-NeuNT 诱发的乳腺肿瘤的发生。 PTP1B 缺陷的影响与复合突变小鼠癌前乳腺中细胞外信号调节激酶激活缺陷相关。相反，PTP1B 缺陷对 MMTV 多瘤中 T 肿瘤发生没有影响。我们的数据提出了 PTP1B 抑制剂可能对某些形式的乳腺癌具有化学预防作用的可能性。
The protein-tyrosine phosphatase 1B (PTP1B; PTPN1) is an important regulator of mammalian metabolism and also helps control signaling by growth factors, cytokines, and extracellular matrix. Gene knockout studies in mice established PTP1B as a key negative regulator of the insulin and leptin receptors. Experiments using PTP1B(-/-) fibroblast lines, dominant-negative mutants, or small interfering RNAs indicate that PTP1B contributes to dephosphorylation of the epidermal growth factor receptor and platelet-derived growth factor receptors as well. However, PTP1B also may have some positive (signal enhancing) roles downstream of some growth factor receptors and integrins. Previous studies indicated that PTP1B is overexpressed in a significant subset of breast and ovarian cancers, especially in those overexpressing HER2/Neu (HER2(+) tumors). However, experiments using tissue culture cells yield conflicting results on the effects of PTP1B in HER2 signaling, leaving the consequences of PTP1B overexpression for breast carcinogenesis unclear. To determine how PTP1B deficiency affects HER2-evoked breast tumorigenesis, we generated mouse mammary tumor virus (MMTV)-NeuNT transgenic mice lacking one or both alleles of PTP1B. Although heterozygous loss of PTP1B has no effect on tumorigenesis, homozygous PTP1B deficiency dramatically delays or prevents the onset of MMTV-NeuNT-evoked breast tumors. The effects of PTP1B deficiency correlate with defective extracellular signal-regulated kinase activation in preneoplastic mammary glands from compound mutant mice. In contrast, PTP1B deficiency has no effect on MMTV-polyoma middle T tumorigenesis. Our data raise the possibility that PTP1B inhibitors may be chemopreventative for some forms of breast cancer.