PDF(Pubmed)
Abstract：
The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.
摘要：
HER4受体对雌激素受体阳性乳腺癌的生长和治疗的影响尚不确定。使用CRISPR/Cas9技术，我们产生了来自HER4阳性MCF-7,T-47D的稳定HER4敲除变体,和ZR-75-1乳腺癌细胞系。我们研究了肿瘤细胞增殖以及他莫昔芬的细胞和分子机制，abemaciclib,AMG232和NRG1处理作为体外HER4的功能。HER4差异影响对他莫昔芬和abemaciclib治疗的细胞反应。最显著的是MCF-7在HER4敲除后的体外敏感性增加和NRG1对细胞增殖的抑制。此外,我们基于MCF-7HER4-野生型和相应的HER4-敲除细胞,评估了人源化肿瘤小鼠(HTM)对他莫昔芬和abemaciclib治疗的反应和免疫效应.没有任何治疗,HER4基因敲除后HTM中MCF-7肿瘤生长增强,提示HER4在临床前但类似人的条件下具有肿瘤抑制作用.这种现象与体内MCF-7中HER2表达增加有关。与HER4无关，abemaciclib和他莫昔芬治疗可显著抑制这些小鼠的肿瘤生长。然而,经abemaciclib治疗的激素受体阳性乳腺癌患者的肿瘤相关mdm2基因拷贝增加或HER4表达显著,无事件生存率降低.显然,HER4的存在影响他莫昔芬和abemaciclib治疗不同雌激素受体阳性乳腺癌细胞的疗效，甚至在不同程度上，并且与接受abemaciclib治疗的患者的不良结局相关。
