ERBB3,也称为HER3,是ERBB家族的酪氨酸激酶跨膜受体。在与神经调节素1(NRG1)结合时,ERBB3优先与HER2(ERBB2)二聚化,反过来在几种癌症类型中诱导侵袭性特征。对乳腺癌患者数据集的分析揭示,较高的ERBB3mRNA表达与基底样乳腺癌的无复发生存期较短相关。尽管在该乳腺癌亚型中ERBB3表达较低。施用神经调节素1β(NRG1β)不会显着影响细胞增殖,也不会影响基底样/三阴性准正常MCF10A乳腺细胞的基础迁移能力,在单层条件下培养。此外,用NRG1β刺激后,细胞形态或基底/肌上皮和管腔标志物的表达均未观察到显着调节。在非粘附条件下,对MCF10A细胞施用NRG1β并没有显著影响细胞存活;然而,它强烈诱导细胞生长为球体(3D生长)。有趣的是,与2D细胞培养物相比,在3D中观察到ERBB3和ERBB2蛋白丰度的显着上调,抗HER2单克隆抗体帕妥珠单抗有效阻止了NRG1β诱导的3D细胞生长。通过对基底样/三阴性乳腺癌细胞模型的分析获得了类似的结果,MDA-MB-468和MDA-MB-231细胞,其中NRG1β诱导不依赖贴壁的细胞生长,这反过来被同时施用抗HER2中和抗体阻止或减少。最后,帕妥珠单抗抑制NRG1β诱导的3D生长的能力也在HER2过表达的MCF10A中进行了评估和证实.我们建议NRG1/ERBB3/ERBB2途径促进基底样乳腺癌细胞的锚定非依赖性生长。重要的是,我们提供的证据表明ERBB2中和,特别是帕妥珠单抗,强烈地抑制了这个过程。我们的结果为基于NRG1/ERBB3/ERBB2信号轴的截获为基底样乳腺癌患者开发新的抗癌策略铺平了道路。
ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.