Miano Carmen, Romaniello Donatella, Mazzeschi Martina, Morselli Alessandra, Da Pra Silvia, Sacchi Francesca, Bongiovanni Chiara, Sgarzi Michela, Pantano Elvira, Lauriola Mattia, D'Uva Gabriele
National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy.
Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.
Front Oncol. 2022 May 18;12:831105. doi: 10.3389/fonc.2022.831105. eCollection 2022.
ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents.
ERBB4是一种酪氨酸激酶受体，据报道它具有致癌和抑癌活性。这些矛盾的作用被认为源于不同的ERBB4同型/异型二聚体和/或异构体。通过对乳腺癌患者进行临床和分子亚型以及ERBB4 mRNA丰度分层，我们在此报告，在HER2富集和管腔A型分子亚型的乳腺癌患者中，较高的ERBB4水平与较长的无复发生存期相关，表明该受体在这些特定亚组中具有癌症保护作用。我们还观察到，与管腔型和三阴性/基底样亚组相比，HER2富集的乳腺癌表达中等水平的ERBB4 mRNA，管腔型和三阴性/基底样亚组分别显示出最高和最低水平。受这些临床数据的启发，我们测试了神经调节蛋白对ERBB4的激活作用，将其作为HER2 +乳腺癌的一种潜在抗癌策略。为此，我们采用了两种HER2 +乳腺癌细胞模型（BT474和SKBR3），它们分别表达中等/高水平和低水平的ERBB4。在用激活ERBB3和ERBB4的神经调节蛋白-1（NRG1）或特异性激活ERBB4的神经调节蛋白-4（NRG4）处理后，对这些细胞模型的细胞增殖和运动能力进行了评估。NRG1和NRG4均单独使用或与抗ERBB2中和抗体（即曲妥珠单抗和帕妥珠单抗）联合使用。用NRG1处理BT474细胞可抑制细胞生长，并降低曲妥珠单抗的抗增殖功效。相比之下，用NRG1处理SKBR3细胞可增加细胞增殖和迁移，并部分或完全削弱曲妥珠单抗和/或帕妥珠单抗的抗增殖/抗迁移作用。重要的是，在这两种细胞系中，用NRG4处理均能显著增强曲妥珠单抗和帕妥珠单抗的抗增殖作用。总的来说，我们在HER2 +乳腺癌细胞中的数据表明，NRG1可能具有促增殖和抗增殖作用，并可能降低抗HER2药物的疗效，而NRG4可能增强抗ERBB2药物的抗增殖作用。我们提出了癌症进展中生长因子领域一个具有启发性的范式转变，建议给予ERBB4配体，如神经调节蛋白-4，作为提高抗ERBB2药物疗效的一种策略。
