Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells
Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells
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DOI：
10.1158/1541-7786.mcr-12-0378
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发表时间：
2013-04-01
影响因子：
5.2
通讯作者：
Aubele, Michaela
中科院分区：
文献类型：
--
作者：
Ludyga, Natalie;Anastasov, Natasa;Aubele, Michaela
乳腺癌是西方世界妇女最常见的恶性肿瘤。乳腺癌的一个突出特征是HER 2和蛋白酪氨酸激酶6（PTK 6）的共同和过表达。根据目前的临床癌症治疗指南，HER 2过表达肿瘤常规使用曲妥珠单抗（一种靶向HER 2的人源化单克隆抗体）治疗。大约30%的HER 2过表达乳腺肿瘤至少在最初对抗HER 2治疗有反应，但这些肿瘤的一个亚组在曲妥珠单抗给药后不久就产生了耐药性。PTK 6靶向治疗尚不存在。在这里，我们首次表明，与HER 2和PTK 6的单一敲低相比，体外同时敲低，特别是在曲妥珠单抗耐药的JIMT-1细胞中，导致关键信号蛋白的磷酸化显著降低：丝裂原活化蛋白激酶1/3（MAPK 1/3，ERK 1/2）和p38 MAPK，以及（第10号染色体上缺失的磷酸酶和张力蛋白同源物）PTEN，它们参与肿瘤发生。此外，双敲低强烈降低了JIMT-1细胞的迁移和侵袭。此外，HER 2和PTK 6的下调导致p27的诱导，并且双重敲低显著降低了JIMT-1和T47 D细胞中的细胞增殖。体内实验显示HER 2或PTK 6敲低后肿瘤生长水平显著降低。我们的研究结果表明了一种新的策略，也用于治疗肿瘤中的曲妥珠单抗耐药性。因此，抑制这两种信号蛋白可能导致更有效地控制乳腺癌。Mol Cancer Res; 11（4）; 381-92. (C)2013年AACR。
Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer. Mol Cancer Res; 11(4); 381-92. (C) 2013 AACR.