HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer.
HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer.
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DOI：
10.1038/cddis.2013.508
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发表时间：
2014-01-02
影响因子：
9
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人表皮生长因子受体-2 （HER2）在乳腺癌中的过度表达与肿瘤侵袭性和不良预后密切相关。最近，在癌细胞中，HER2与MIF（巨噬细胞迁移抑制因子，一种促瘤蛋白和热休克蛋白90 （HSP90）客户端）蛋白水平呈正相关。然而，潜在的机制联系仍然未知。在这里，我们发现过表达的HER2组成性地激活热休克因子1 (HSF1)，热休克因子1是热休克伴侣（包括HSP90）诱导蛋白毒性应激反应的主要转录调节因子，也是恶性状态启动和维持的关键因素。通过拉帕替尼（一种双重HER2/表皮生长因子受体抑制剂）或CP724.714（一种特异性HER2抑制剂）或通过siRNA敲低抑制HER2，可抑制磷酸化激活的Ser326 HSF1，并随后阻断HER2过表达乳腺癌细胞系中HSP90伴侣机制的活性。因此，HSP90客户端，包括MIF、AKT、突变型p53和HSF1本身，变得不稳定，从而抑制肿瘤增殖。从机制上讲，HER2信号通过磷酸肌醇-3-激酶(PI3K) - akt -哺乳动物雷帕霉素靶点（mTOR）轴诱导激活pSer326 HSF1。热休克应激实验证实了HER2和HSF1之间的这种功能联系，因为HER2（和PI3K）的抑制减弱了HSF1介导的热休克反应。重要的是，我们在体内证实了这个轴。在her2驱动的乳腺癌小鼠模型中，拉帕替尼抑制ErbB2强烈抑制肿瘤进展，这与HSF1通路失活有关。此外，来源于小鼠原发ErbB2肿瘤的过表达ErbB2的癌细胞在ErbB2抑制下也表现出HSF1失活和HSP90客户端不稳定。此外，在HER2阳性的人乳腺癌中，HER2水平与pSer326 HSF1活性密切相关。我们的研究结果首次表明HER2/ErbB2过表达控制HSF1活性，随后稳定了许多促进肿瘤的HSP90客户，如MIF、AKT和HSF1本身，从而导致HER2阳性乳腺癌中肿瘤生长的强劲促进。
Overexpression of the human epidermal growth factor receptor-2 (HER2) in breast cancer strongly correlates with aggressive tumors and poor prognosis. Recently, a positive correlation between HER2 and MIF (macrophage migration inhibitory factor, a tumor-promoting protein and heat-shock protein 90 (HSP90) client) protein levels was shown in cancer cells. However, the underlying mechanistic link remained unknown. Here we show that overexpressed HER2 constitutively activates heat-shock factor 1 (HSF1), the master transcriptional regulator of the inducible proteotoxic stress response of heat-shock chaperones, including HSP90, and a crucial factor in initiation and maintenance of the malignant state. Inhibiting HER2 pharmacologically by Lapatinib (a dual HER2/epidermal growth factor receptor inhibitor) or CP724.714 (a specific HER2 inhibitor), or by knockdown via siRNA leads to inhibition of phosphoactivated Ser326 HSF1, and subsequently blocks the activity of the HSP90 chaperone machinery in HER2-overexpressing breast cancer lines. Consequently, HSP90 clients, including MIF, AKT, mutant p53 and HSF1 itself, become destabilized, which in turn inhibits tumor proliferation. Mechanistically, HER2 signals via the phosphoinositide-3-kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) axis to induce activated pSer326 HSF1. Heat-shock stress experiments confirm this functional link between HER2 and HSF1, as HER2 (and PI3K) inhibition attenuate the HSF1-mediated heat-shock response. Importantly, we confirmed this axis in vivo. In the mouse model of HER2-driven breast cancer, ErbB2 inhibition by Lapatinib strongly suppresses tumor progression, and this is associated with inactivation of the HSF1 pathway. Moreover, ErbB2-overexpressing cancer cells derived from a primary mouse ErbB2 tumor also show HSF1 inactivation and HSP90 client destabilization in response to ErbB2 inhibition. Furthermore, in HER2-positive human breast cancers HER2 levels strongly correlate with pSer326 HSF1 activity. Our results show for the first time that HER2/ErbB2 overexpression controls HSF1 activity, with subsequent stabilization of numerous tumor-promoting HSP90 clients such as MIF, AKT and HSF1 itself, thereby causing a robust promotion in tumor growth in HER2-positive breast cancer.