Carpenter Richard L, Lo Hui-Wen
Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA.
Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, North Carolina 27710, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina 27710, USA.
J Carcinog Mutagen. 2013;2013(Suppl 7). doi: 10.4172/2157-2518.S7-003. Epub 2013 Jun 26.
HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.
人表皮生长因子受体2（HER2）是一种跨膜受体酪氨酸激酶，可激活多种促进生长的信号通路，包括PI3K-AKT和Ras-MAPK。HER2失调在乳腺癌中经常发生，这与患者预后不良有关。HER2的主要功能是抑制细胞凋亡以提高细胞存活率，从而导致不受控制的增殖和肿瘤生长。人们对HER2抑制细胞凋亡的机制进行了大量研究，希望找到HER2阳性乳腺癌的临床靶点，因为这些癌症通常会对直接靶向HER2的疗法产生耐药性。在HER2过表达的细胞中，几种凋亡机制已被证明失调，内在和外在凋亡途径均有实例。HER2介导的PI3K-AKT信号激活是HER2用于抑制细胞凋亡的许多机制所必需的。HER2过表达与抗凋亡Bcl-2蛋白（包括Bcl-2、Bcl-xL和Mcl-1）的增加相关。HER2还通过激活AKT上调MDM2来抑制p53介导的细胞凋亡。此外，随着HER2过表达，生存素表达通常会增加，导致半胱天冬酶激活受到抑制。最近也有证据表明，HER2可通过转位至线粒体以抑制细胞色素释放来直接影响细胞凋亡。HER2还可抑制细胞对死亡配体的反应，尤其是肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的细胞凋亡。对HER2抑制细胞凋亡机制的阐明表明，临床治疗可能需要针对这些途径的多个成分，因为HER2介导的细胞存活存在冗余。几种疗法已尝试靶向Bcl-2蛋白，这些疗法在临床前研究中取得了有前景的结果。下一代HER2靶向疗法包括不可逆的泛表皮生长因子受体（ERBB）抑制剂和抗体药物偶联物，如曲妥珠单抗-美坦新偶联物（T-DM1），迄今为止其临床结果非常有前景。进一步的研究应包括阐明对HER2靶向疗法的耐药机制以及靶向HER2介导的细胞存活的多个成分。
