Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, Korea.
Department of Radiation Oncology, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Int J Mol Sci. 2019 Oct 7;20(19):4943. doi: 10.3390/ijms20194943.
Proton therapy offers a distinct physical advantage over conventional X-ray therapy, but its biological advantages remain understudied. In this study, we aimed to identify genetic factors that contribute to proton sensitivity in breast cancer (BC). Therefore, we screened relative biological effectiveness (RBE) of 230 MeV protons, compared to 6 MV X-rays, in ten human BC cell lines, including five triple-negative breast cancer (TNBC) cell lines. Clonogenic survival assays revealed a wide range of proton RBE across the BC cell lines, with one out of ten BC cell lines having an RBE significantly different from the traditional generic RBE of 1.1. An abundance of cyclin D1 was associated with proton RBE. Downregulation of RB1 by siRNA or a CDK4/6 inhibitor increased proton sensitivity but not proton RBE. Instead, the depletion of cyclin D1 increased proton RBE in two TNBC cell lines, including MDA-MB-231 and Hs578T cells. Conversely, overexpression of cyclin D1 decreased the proton RBE in cyclin D1-deficient BT-549 cells. The depletion of cyclin D1 impaired proton-induced RAD51 foci formation in MDA-MB-231 cells. Taken together, this study provides important clues about the cyclin D1-CDK4-RB1 pathway as a potential target for proton beam therapy in TNBC.
质子治疗相对于传统的 X 射线治疗具有明显的物理优势，但它的生物学优势仍在研究中。在这项研究中，我们旨在确定导致乳腺癌（BC）对质子敏感的遗传因素。因此，我们筛选了 230 MeV 质子与 6 MV X 射线相比在十种人乳腺癌细胞系中的相对生物效应（RBE），包括五种三阴性乳腺癌（TNBC）细胞系。集落形成生存分析显示，在 BC 细胞系中质子 RBE 范围广泛，十种 BC 细胞系中有一种的 RBE 与传统的通用 RBE（1.1）显著不同。大量的细胞周期蛋白 D1 与质子 RBE 相关。用 siRNA 或 CDK4/6 抑制剂下调 RB1 增加了质子敏感性，但没有增加质子 RBE。相反，在两种 TNBC 细胞系，包括 MDA-MB-231 和 Hs578T 细胞中，细胞周期蛋白 D1 的耗竭增加了质子 RBE。相反，在细胞周期蛋白 D1 缺陷的 BT-549 细胞中过表达细胞周期蛋白 D1 降低了质子 RBE。细胞周期蛋白 D1 的耗竭破坏了 MDA-MB-231 细胞中质子诱导的 RAD51 焦点形成。综上所述，这项研究为细胞周期蛋白 D1-CDK4-RB1 途径作为 TNBC 质子束治疗的潜在靶点提供了重要线索。
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