College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Department of Oral & Maxillofacial Pathology, College of Dentistry, Daejeon Dental Hospital, Wonkwang University, Daejeon, South Korea.
Mol Cancer Ther. 2018 Apr;17(4):825-837. doi: 10.1158/1535-7163.MCT-17-0545. Epub 2018 Feb 7.
The most common therapy for estrogen receptor-positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G-M phase of the cell cycle. We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in tamoxifen-resistant MCF-7 (TAMR-MCF-7) breast cancer cells. Real-time monitoring of cell proliferation also showed that TAMR-MCF-7 cells were more sensitive to inhibition of cell proliferation by the ATP-competitive Plk1 inhibitor BI2536 than were the parent MCF-7 cells. Moreover, BI2536 suppressed expression of epithelial-mesenchymal transition marker proteins and 3D spheroid formation in TAMR-MCF-7 cells. Using TAMR-MCF-7 cell-implanted xenograft and spleen-liver metastasis models, we showed that BI2536 inhibited tumor growth and metastasis Our results suggest that Plk1 could be a novel target for the treatment of tamoxifen-resistant breast cancer. .
最常见的治疗雌激素受体阳性乳腺癌的方法是抗激素治疗，如他莫昔芬。然而，三分之一的患者对他莫昔芬产生耐药性是一个严重的临床问题。Polo 样激酶 1（Plk1）是细胞周期 G2-M 期完成的关键致癌调节因子。我们评估了五种耐药性癌细胞类型中的 Plk1 表达，发现 Plk1 及其下游磷酸酶 Cdc25c 在他莫昔芬耐药 MCF-7（TAMR-MCF-7）乳腺癌细胞中选择性过表达。细胞增殖的实时监测还表明，TAMR-MCF-7 细胞对 ATP 竞争性 Plk1 抑制剂 BI2536 抑制细胞增殖的敏感性高于亲本 MCF-7 细胞。此外，BI2536 抑制了 TAMR-MCF-7 细胞中上皮-间充质转化标记蛋白的表达和 3D 球体形成。使用 TAMR-MCF-7 细胞植入的异种移植和脾-肝转移模型，我们表明 BI2536 抑制了肿瘤生长和转移。我们的研究结果表明，Plk1 可能成为治疗他莫昔芬耐药性乳腺癌的新靶点。
