Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression
Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression
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DOI：
10.1158/1535-7163.mct-07-0370
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发表时间：
2008-01-01
影响因子：
5.7
通讯作者：
Devi, Gayathri R.
中科院分区：
文献类型：
--
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
炎症性乳腺癌(IBC)患者存活率低，表皮生长因子受体-2(ErbB2)高表达的发生率较高。在ERbB2高表达、雌激素受体阴性的IBC瘤细胞模型SUM190PT中，观察到一种独特的机制，涉及X连锁的凋亡抑制蛋白[XIAP]和Survivin的表达增加，后者是IAP家族的关键成员。相反，在非IBC、ErbB2过表达的SKBR3细胞中观察到IAP的表达减少，其中曲妥珠单抗处理也降低了p-AKT和细胞存活率。此外，在SUM190PT细胞中，对GW583340(一种双重表皮生长因子受体/ErbB2激酶抑制剂)的治疗敏感性与XIAP下调和XIAP对caspase-9活性释放的抑制作用相一致。在具有高稳态p-AKT水平的SUM190PT细胞中，特异性小干扰RNA介导的XIAP抑制与曲妥珠单抗联合应用可导致失活的p-AKT酶-9活性降低和p-AKT抑制，相应地细胞存活率下降45%-50%。此外，Embelin是一种小分子抑制剂，可以取消XIAP与proaspase-9的结合，导致SUM190PT活性显著下降。然而，恩贝林与曲妥珠单抗联合应用对曲妥珠单抗诱导的XIAP无直接影响，因此未能影响SUM190PT的活性。这些数据证实了ErbB2信号与XIAP介导的抗细胞凋亡途径之间的一个新的功能联系。在IBC治疗中，单独或联合阻断IAP抗凋亡通路将是一个有吸引力的策略。
Inflammatory breast cancer (IBC) patients show poor survival and a significant incidence of epidermal growth factor receptor-2 (ErbB2) overexpression. A distinct mechanism involving increased expression of X-linked inhibitor of apoptosis protein [XIAP) and survivin, key members of the inhibitor of apoptosis protein (IAP) family, was observed post-trastuzumab (an ErbB2 monoclonal antibody) treatment in an ErbB2-overexpressing, estrogen receptor negative, IBC cellular model, SUM190PT, isolated from a primary IBC tumor. In contrast, a decrease in the IAP expression was observed in the non-IBC, ErbB2-overexpressing SKBR3 cells in which trastuzumab treatment also decreased p-AKT and cell viability. Further, in SUM190PT cells, therapeutic sensitivity to GW583340 (a dual epidermal growth factor receptor/ErbB2 kinase inhibitor) corresponded with XIAP down-regulation and abrogation of XIAP inhibition on active caspase-9 release. Specific small interfering RNA-mediated XIAP inhibition in combination with trastuzumab caused decrease in inactive procaspase-9 and inhibition of p-AKT corresponding with 45% to 50% decrease in cell viability in the SUM190PT cells, which have high steady-state p-AKT levels. Further, embelin, a small-molecule inhibitor that abrogates binding of XIAP to procaspase-9, caused significant decrease in SUM190PT viability. However, embelin in combination with trastuzumab failed to affect SUM190PT viability because it has no direct effect on XIAP, which is induced by trastuzumab treatment. These data have identified a novel functional link between ErbB2 signaling and antiapoptotic pathway mediated by XIAP. Blockade of the IAP antiapoptotic pathway alone or in combination would be an attractive strategy in IBC therapy.