McGill University, Lady Davis Institute & Segal Cancer Center, Jewish General Hospital, Montreal, Canada.
PLoS One. 2011 Jan 24;6(1):e16394. doi: 10.1371/journal.pone.0016394.
Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3) and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over-expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell-cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion.
DNA 修复基因的过度表达与辐射抗性和化疗药物（如顺铂）引起的 DNA 损伤有关。最近，基于基因组表达谱分析，有人提出 DNA 修复基因的过度表达增强了肿瘤细胞的侵袭行为。在这项研究中，我们利用功能测定提供了实验证据来验证这一假设。我们评估了已知的 X 射线修复互补蛋白 3（XRCC3）和 RAD51 等 DNA 修复蛋白对 MCF-7 腔上皮样和 BT20 基底样三阴性人乳腺癌细胞系侵袭行为的影响。我们报告说，XRCC3 的稳定或瞬时过表达增加了这两种细胞系在体外的侵袭性。此外，XRCC3 过表达的 MCF-7 细胞在体内也显示出更高的致瘤性，这种表型与基质金属蛋白酶 MMP-9 活性的增加以及细胞间黏附与转移的已知调节剂（如 CD44、ID-1、DDR1 和 TFF1）的表达有关。我们的结果表明，除了在促进 DNA 损伤修复中的作用外，XRCC3 还影响乳腺癌细胞系的侵袭性以及与细胞黏附和侵袭相关的基因表达。
