Radboud University Medical Center, Department of Radiation Oncology, Radiotherapy and OncoImmunology LaboratoryNijmegenThe Netherlands.
Radboud University Medical Center, Department of Laboratory MedicineNijmegenThe Netherlands.
Oncol Res. 2020 Feb 7;28(1):33-40. doi: 10.3727/096504019X15555794826018. Epub 2019 Apr 18.
Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated ( and ), and three DNA damage repair genes were more than two times downregulated (, , and ). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G, G/S, G₂, and G₂/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated () or downregulated (, , , , , and ) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.
他莫昔芬诱导的放射抵抗，在体外已有所报道，这可能会给接受新辅助他莫昔芬治疗、随后在手术后接受放疗的患者带来问题。先前的研究表明，涉及 DNA 损伤修复或细胞周期基因，因此可以靶向这些基因以防止交叉耐药的发生。我们旨在通过研究雌激素受体阳性 MCF-7 乳腺癌细胞中培养至他莫昔芬耐药的 DNA 损伤修复基因和细胞周期基因的表达特征来描述观察到的交叉耐药。进行了 RNA 测序，并研究了几种 DNA 损伤修复途径的特征基因的表达，以及参与细胞周期不同阶段的基因的表达。在一个大型乳腺癌队列中，通过计算机模拟评估差异表达基因与放疗后结果的相关性。与野生型细胞相比，耐药细胞中没有任何 DNA 损伤修复途径显示出差异表达的基因。两个 DNA 损伤修复基因上调超过两倍（和），三个 DNA 损伤修复基因下调超过两倍（、和）。然而，在 TCGA 乳腺癌队列中，这些基因与放疗后的结果无关。与野生型细胞相比，耐药细胞中参与 G、G/S、G₂和 G₂/M 期的基因表达水平较低。上调超过两倍（）或下调超过两倍（、、、、、和）的个别基因与患者队列中放疗反应无关。我们评估了他莫昔芬耐药乳腺癌细胞中 DNA 损伤修复基因和细胞周期基因的表达。尽管两条途径中的几个基因表达存在差异，但这些基因不能解释这些细胞对辐射的交叉耐药性，因为在 TCGA 乳腺癌队列中没有发现与放疗反应相关的基因。
