近日，来自德国的科学家发现HER2二聚体在一小群休眠的SKBR3乳腺癌细胞中发生缺失，这一群细胞具有自我更新的特性，可能在靶向HER2的抗体治疗过程中促进了乳腺癌细胞对此类抗体药物的抵抗，导致新的肿瘤形成。
HER2是属于EGFR受体家族的一类膜蛋白，通常情况下当该家族成员受到外界信号刺激，可以形成二聚体，触发细胞生长信号，但HER2比较特别，其可以在没有外界信号刺激的情况下发生二聚化调节细胞生长。在之前一些研究中发现HER2在一些特定类型的乳腺癌中发挥重要作用：HER2表达水平增加会导致细胞发生无限生长。目前有一些靶向HER2的抗体疗法可以发挥阻止癌细胞生长的作用，但有大约三分之二的HER2阳性乳腺癌病人会对HER2靶向性药物产生抵抗，其中的原因一直不明。
在这项研究中，研究人员利用荧光显微镜和环境扫描电子显微镜技术在纳米水平上对液体环境下的完整细胞结构进行了研究。他们将细胞接种在微芯片上，使细胞处于液体环境中，随后将微芯片放在电子显微镜下进行观察，这种方法克服了传统电镜方法无法对液体环境下完整细胞进行观察的技术障碍。
利用这种新技术研究人员对HER2膜蛋白的局部改变及其二聚体的形成进行了观察，结果发现在一小群休眠的SKBR3细胞中，HER2二聚体会发生缺失。但这一小群细胞是否在靶向治疗过程中存活下来并在乳腺癌后期导致药物抵抗的发生还需要更多的研究进行证明。
生物谷小编认为这项研究利用一种新的电子显微镜技术对乳腺癌细胞膜上的HER2进行了观察，在一小群休眠的SKBR3乳腺癌细胞中发现存在HER2二聚体缺失，并提出这可能是导致乳腺癌病人抵抗HER2抗体靶向疗法的重要原因。
相关研究结果发表在国际学术期刊science advances上。
Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy
Diana B. Peckys1, Ulrike Korf2 and Niels de Jonge
The formation of HER2 homodimers plays an important role in breast cancer aggressiveness and progression; however, little is known about its localization. We have studied the intra- and intercellular variation of HER2 at the single-molecule level in intact SKBR3 breast cancer cells. Whole cells were visualized in hydrated state with correlative fluorescence microscopy and environmental scanning electron microscopy (ESEM). The locations of individual HER2 receptors were detected using an anti-HER2 affibody in combination with a quantum dot (QD), a fluorescent nanoparticle. Fluorescence microscopy revealed considerable differences of HER2 membrane expression between individual cells and between different membrane regions of the same cell (that is, membrane ruffles and flat areas). Subsequent ESEM of the corresponding cellular regions provided images of individually labeled HER2 receptors. The high spatial resolution of 3 nm and the close proximity between the QD and the receptor allowed quantifying the stoichiometry of HER2 complexes, distinguishing between monomers, dimers, and higher-order clusters. Downstream data analysis based on calculating the pair correlation function from receptor positions showed that cellular regions exhibiting membrane ruffles contained a substantial fraction of HER2 in homodimeric state. Larger-order clusters were also present. Membrane areas with homogeneous membrane topography, on the contrary, displayed HER2 in random distribution. Second, HER2 homodimers appeared to be absent from a small subpopulation of cells exhibiting a flat membrane topography, possibly resting cells. Local differences in homodimer presence may point toward functional differences with possible relevance for studying metastasis and drug response.