Centre de recherche sur le cancer, Centre de recherche du CHU de Québec-Université Laval, Québec, Canada.
Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec, Canada.
PLoS One. 2020 Jun 25;15(6):e0234991. doi: 10.1371/journal.pone.0234991. eCollection 2020.
The breast cancer (BC) biomarker HER2 (Human Epidermal Receptor 2) is overexpressed in 25% of BC. Only patients with HER2-positive tumors receive HER2-targeting therapies, like trastuzumab (Herceptin). However, some women with a HER2-negative BC could benefit from trastuzumab. This could be explained by the activation/phosphorylation of HER2 that can be recognized by trastuzumab. The aim of this study is to examine trastuzumab effects on HER2 phosphorylation at tyrosine Y877 (pHER2Y877). HER2 and pHER2Y877 status were evaluated in a cohort of BC patients representative of molecular subtypes distribution (n = 497) and in a series of BC cell lines (n = 7). Immunohistochemistry against pHER2Y877 was performed on tissue micro arrays. Cellular proliferation assays were performed on BC cell lines presenting different combinations of HER2 and pHER2Y877 status and treated with increasing doses of trastuzumab (0-150 μg/ml). The prevalence of pHER2Y877 in this cohort was 6%. Nearly 5% of patients with HER2-negative tumors (n = 406, 82%) overexpressed pHER2Y877. Among triple negative BC patients (n = 39, 8%), 7.7% expressed pHER2Y877. Trastuzumab treatment decreased cell proliferation in HER2-/pHER2Y877+ BC cell lines, to an extent comparable to what occurs in HER2+ cell lines, but did not affect HER2-/pHER2Y877- cell lines. Trastuzumab sensitivity in HER2-/pHER2Y877+ cell line is specific to HER2 tyrosine 877 phosphorylation. Hence, with further confirmation in a bigger cohort, trastuzumab treatment could be envisaged as a treatment option to women presenting with HER2-/pHER2+ tumors, representing more than 1000 BC women in Canada in 2019.
乳腺癌（BC）标志物 HER2（人表皮受体 2）在 25%的 BC 中过表达。只有 HER2 阳性肿瘤的患者才会接受 HER2 靶向治疗，如曲妥珠单抗（赫赛汀）。然而，一些 HER2 阴性的 BC 女性可能会从曲妥珠单抗中受益。这可以通过 HER2 的激活/磷酸化来解释，曲妥珠单抗可以识别这种磷酸化。本研究旨在研究曲妥珠单抗对酪氨酸 Y877 磷酸化的 HER2（pHER2Y877）的作用。在具有代表性的分子亚型分布的 BC 患者队列（n = 497）和一系列 BC 细胞系（n = 7）中评估了 HER2 和 pHER2Y877 状态。对组织微阵列进行了针对 pHER2Y877 的免疫组织化学染色。在具有不同 HER2 和 pHER2Y877 状态组合的 BC 细胞系上进行了细胞增殖测定，并使用递增剂量的曲妥珠单抗（0-150μg/ml）进行了处理。在该队列中，pHER2Y877 的患病率为 6%。近 5%的 HER2 阴性肿瘤患者（n = 406，82%）过表达 pHER2Y877。在三阴性 BC 患者中（n = 39，8%），有 7.7%表达 pHER2Y877。曲妥珠单抗治疗降低了 HER2-/pHER2Y877+BC 细胞系的细胞增殖，其程度与 HER2+细胞系相似，但不影响 HER2-/pHER2Y877-细胞系。HER2-/pHER2Y877+细胞系对曲妥珠单抗的敏感性是 HER2 酪氨酸 877 磷酸化特异性的。因此，在更大的队列中进一步确认后，曲妥珠单抗治疗可能被视为一种治疗选择，适用于 2019 年加拿大超过 1000 名 HER2-/pHER2+肿瘤女性患者。
