Zhai Y F, Beittenmiller H, Wang B, Gould M N, Oakley C, Esselman W J, Welsch C W
Department of Pharmacology, Michigan State University, East Lansing 48824.
Cancer Res. 1993 May 15;53(10 Suppl):2272-8.
Protein tyrosine phosphorylation/dephosphorylation is a fundamental mechanism in the regulation of cell proliferation and neoplastic transformation; this metabolic process is modulated by the opposing activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases). While the role of protein tyrosine kinases has been examined extensively in human breast tumorigenesis, the role of PTPases in this process is virtually unknown. To address this issue, an activated neu oncogene was introduced into an immortalized nontumorigenic human breast epithelial cell line (184B5). This resulted in a substantial increase in P185neu expression, which led to the formation of progressively growing carcinomas after such cells were inoculated into athymic nude mice. Importantly, a striking increase in the expression of specific PTPases, LAR and PTP1B, was observed in 3 independently neu transformed cell lines and their derived tumors. This elevation was verified at both the mRNA and protein levels. TC-PTP PTPase expression was only slightly increased in these neu transformed cells, and no expression of CD45 PTPase was observed. The level of neu expression, as well as the differential expression between P185neu and LAR/PTP1B, directly correlated with tumorigenicity. Furthermore, rat mammary carcinomas with elevated neu expression (neu-induced) also had sharply elevated LAR-PTPase expression when compared to rat mammary carcinomas with little or no neu expression (7,12-dimethylbenzanthracene induced); the level of expression of LAR PTPase was directly correlated with the level of neu expression. Thus, our results provide the first evidence that, in human breast carcinoma cells and in rat mammary carcinomas that have an induced increase in neu expression, a consistent and substantial increase in the expression of specific PTPases occurs. The relationship between P185neu-protein tyrosine kinase expression and specific PTPase expression may play a critical role in human breast tumorigenesis.
蛋白质酪氨酸磷酸化/去磷酸化是调节细胞增殖和肿瘤转化的基本机制；这一代谢过程由蛋白质酪氨酸激酶和蛋白质酪氨酸磷酸酶（PTPases）的相反活性调节。虽然蛋白质酪氨酸激酶在人类乳腺肿瘤发生中的作用已得到广泛研究，但PTPases在此过程中的作用几乎未知。为了解决这个问题，将活化的neu癌基因导入永生化的非致瘤性人乳腺上皮细胞系（184B5）。这导致P185neu表达大幅增加，将这些细胞接种到无胸腺裸鼠中后，导致逐渐生长的癌形成。重要的是，在3个独立的neu转化细胞系及其衍生肿瘤中观察到特定PTPases（LAR和PTP1B）的表达显著增加。这种升高在mRNA和蛋白质水平均得到证实。在这些neu转化细胞中，TC-PTP PTPase表达仅略有增加，未观察到CD45 PTPase的表达。neu表达水平以及P185neu与LAR/PTP1B之间的差异表达与致瘤性直接相关。此外，与neu表达很少或无neu表达的大鼠乳腺癌（7,12-二甲基苯并蒽诱导）相比，neu表达升高（neu诱导）的大鼠乳腺癌中LAR-PTPase表达也急剧升高；LAR PTPase的表达水平与neu表达水平直接相关。因此，我们的结果提供了首个证据，即在人乳腺癌细胞和neu表达诱导增加的大鼠乳腺癌中，特定PTPases的表达持续且大幅增加。P185neu-蛋白质酪氨酸激酶表达与特定PTPase表达之间的关系可能在人类乳腺肿瘤发生中起关键作用。
