Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer.
Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer.
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DOI：
10.1186/bcr2328
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Streuli CH
中科院分区：
文献类型：
--
作者：
Foster FM;Owens TW;Tanianis-Hughes J;Clarke RB;Brennan K;Bundred NJ;Streuli CH
细胞凋亡抑制因子（IAP）蛋白是一类能够阻断正常细胞凋亡的蛋白质家族，并被认为在癌症中引起对细胞凋亡的抵抗。致癌受体酪氨酸激酶的过表达在乳腺癌中很常见;特别是20%的病例显示Her2升高。尽管使用靶向治疗（如曲妥珠单抗）取得了临床成功，但只有高达35%的Her2阳性患者最初有反应。我们推断IAP介导的凋亡抵抗可能导致对受体酪氨酸激酶治疗的不敏感性，特别是ErbB拮抗剂。在这里，我们检查了乳腺癌中IAP的水平，并评估靶向IAP是否可以增强细胞凋亡以响应生长因子受体拮抗剂和肿瘤坏死因子相关凋亡配体。在乳腺癌细胞系组和患者样品中检查IAP水平。使用siRNA或内源性抑制剂的细胞可渗透模拟物抑制IAP。然后将细胞暴露于TRAIL、曲妥珠单抗、拉帕替尼或吉非替尼48小时。检查细胞核形态和染色裂解的半胱天冬酶3用于对细胞凋亡进行评分。Ki67染色检测细胞增殖。IAP家族的四个成员Survivin、XIAP、cIAP 1和cIAP 2在乳腺癌细胞系或肿瘤中都有不同程度的表达。MDAMB 468、BT 474和BT 20细胞均不同程度地表达XIAP。耗尽XIAP的细胞克服了BT20和MDAMB 468细胞对TRAIL的内在抗性。此外，XIAP的基于siRNA的消耗或靶向多个IAP的Smac模拟物的使用增加了响应于ErbB拮抗剂、Her2过表达的BT474细胞中的曲妥珠单抗、拉帕替尼或吉非替尼或EGFR过表达的MDAMB 468细胞中的吉非替尼的细胞凋亡。本研究的新发现是，多种IAP在乳腺癌中伴随表达，并且与临床相关的Her2治疗组合，IAP拮抗剂促进细胞凋亡并降低乳腺癌的细胞更新指数。我们还表明，IAP拮抗剂与一些促凋亡剂（例如，TRAIL）的联合治疗增强了乳腺癌细胞的凋亡。在某些情况下（例如，MDAMB 468细胞），增强的细胞凋亡是深刻的。
Inhibitor of apoptosis (IAPs) proteins are a family of proteins that can block apoptosis in normal cells and have been suggested to cause resistance to apoptosis in cancer. Overexpression of oncogenic receptor tyrosine kinases is common in breast cancer; in particular 20% of all cases show elevated Her2. Despite clinical success with the use of targeted therapies, such as Trastuzumab, only up to 35% of Her2-positive patients initially respond. We reasoned that IAP-mediated apoptosis resistance might contribute to this insensitivity to receptor tyrosine kinase therapy, in particular ErbB antagonists. Here we examine the levels of IAPs in breast cancer and evaluate whether targeting IAPs can enhance apoptosis in response to growth factor receptor antagonists and TRAIL. IAP levels were examined in a breast cancer cell line panel and in patient samples. IAPs were inhibited using siRNA or cell permeable mimetics of endogenous inhibitors. Cells were then exposed to TRAIL, Trastuzumab, Lapatinib, or Gefitinib for 48 hours. Examining nuclear morphology and staining for cleaved caspase 3 was used to score apoptosis. Proliferation was examined by Ki67 staining. Four members of the IAP family, Survivin, XIAP, cIAP1 and cIAP2, were all expressed to varying extents in breast cancer cell lines or tumours. MDAMB468, BT474 and BT20 cells all expressed XIAP to varying extents. Depleting the cells of XIAP overcame the intrinsic resistance of BT20 and MDAMB468 cells to TRAIL. Moreover, siRNA-based depletion of XIAP or use of a Smac mimetic to target multiple IAPs increased apoptosis in response to the ErbB antagonists, Trastuzumab, Lapatinib or Gefitinib in Her2-overexpressing BT474 cells, or Gefitinib in EGFR-overexpressing MDAMB468 cells. The novel findings of this study are that multiple IAPs are concomitantly expressed in breast cancers, and that, in combination with clinically relevant Her2 treatments, IAP antagonists promote apoptosis and reduce the cell turnover index of breast cancers. We also show that combination therapy of IAP antagonists with some pro-apoptotic agents (for example, TRAIL) enhances apoptosis of breast cancer cells. In some cases (for example, MDAMB468 cells), the enhanced apoptosis is profound.
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影响因子：
5.7
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
通讯作者：
Devi, Gayathri R.
Survivin 是预后不良的乳腺癌患者短期生存的独立预测因子。
影响因子：
8.8
作者：
通讯作者：
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影响因子：
50.5
作者：
Ferreira, CG;van der Valk, P;Giaccone, G
通讯作者：
Giaccone, G
影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
Wang, XD
影响因子：
6.2
作者：
Kos, KS;Zhou, XY;Yu, DH
通讯作者：
Yu, DH