Signal Transduction Research Group, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Cells. 2022 Dec 16;11(24):4093. doi: 10.3390/cells11244093.
To improve the efficacy of trastuzumab, it is essential to understand its mechanism of action. One of the significant issues that makes it difficult to determine the precise mechanism of trastuzumab action is the formation of various HER receptor dimers in HER2-positive breast cancer cells. So far, studies have focused on the role of HER2-HER3 heterodimers, and little is known regarding EGFR-HER2 heterodimers. Here, we study the role of trastuzumab on the cell signaling and cell proliferation mediated by EGFR-HER2 heterodimers in BT474 and SRBR3 cells. EGF stimulates the formation of both EGFR homodimer and EGFR-HER2 heterodimer. Trastuzumab only binds to HER2, not EGFR. Therefore, any effects of trastuzumab on EGF-induced activation of EGFR, HER2, and downstream signaling proteins, as well as cell proliferation, are through its effects on EGFR-HER2 heterodimers. We show that trastuzumab inhibits EGF-induced cell proliferation and cell cycle progression in BT474 and SKBR3 cells. Interestingly trastuzumab strongly inhibits EGF-induced Akt phosphorylation and slightly inhibits EGF-induced Erk activation, in both BT474 and SKBR3 cells. These data suggest the presence of a novel mechanism that allows trastuzumab to inhibit EGR-induced Akt activation and cell proliferation, without blocking EGF-induced EGFR-HER2 heterodimerization and activation. We show that trastuzumab inhibits EGF-induced lipid raft localization of the EGFR-HER2 heterodimer. Disruption of the lipid raft with MβCD blocks HER2-mediated AKT activation in a similar way to trastuzumab. MβCD and trastuzumab synergically inhibit AKT activation. We conclude that trastuzumab inhibits EGF-induced lipid raft localization of EGFR-HER2 heterodimer, which leads to the inhibition of Akt phosphorylation and cell proliferation, without blocking the formation and phosphorylation of the EGFR-HER2 heterodimer.
为了提高曲妥珠单抗的疗效，了解其作用机制至关重要。曲妥珠单抗作用的确切机制难以确定的一个重要问题是，HER2 阳性乳腺癌细胞中各种 HER 受体二聚体的形成。到目前为止，研究主要集中在 HER2-HER3 异二聚体的作用上，而对于 EGFR-HER2 异二聚体知之甚少。在这里，我们研究了曲妥珠单抗在 BT474 和 SRBR3 细胞中对 EGFR-HER2 异二聚体介导的细胞信号转导和细胞增殖的作用。EGF 刺激 EGFR 同源二聚体和 EGFR-HER2 异二聚体的形成。曲妥珠单抗仅与 HER2 结合，不与 EGFR 结合。因此，曲妥珠单抗对 EGF 诱导的 EGFR、HER2 和下游信号蛋白激活以及细胞增殖的任何影响都是通过其对 EGFR-HER2 异二聚体的影响。我们表明，曲妥珠单抗抑制 BT474 和 SKBR3 细胞中 EGF 诱导的细胞增殖和细胞周期进程。有趣的是，曲妥珠单抗强烈抑制 BT474 和 SKBR3 细胞中 EGF 诱导的 Akt 磷酸化，轻度抑制 EGF 诱导的 Erk 激活。这些数据表明存在一种新的机制，允许曲妥珠单抗抑制 EGR 诱导的 Akt 激活和细胞增殖，而不阻断 EGF 诱导的 EGFR-HER2 异二聚体化和激活。我们表明，曲妥珠单抗抑制 EGF 诱导的 EGFR-HER2 异二聚体的脂筏定位。用 MβCD 破坏脂筏以类似于曲妥珠单抗的方式阻断 HER2 介导的 AKT 激活。MβCD 和曲妥珠单抗协同抑制 AKT 激活。我们得出结论，曲妥珠单抗抑制 EGF 诱导的 EGFR-HER2 异二聚体的脂筏定位，导致 Akt 磷酸化和细胞增殖的抑制，而不阻断 EGFR-HER2 异二聚体的形成和磷酸化。
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