Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
J Hum Genet. 2009 Nov;54(11):647-54. doi: 10.1038/jhg.2009.89. Epub 2009 Sep 18.
We investigated the effect of the mitochondrial DNA (mtDNA) polymorphism G10398A found in African-American women with aggressive breast cancer on apoptosis and tumorigenesis. We generated human cytoplasmic hybrid (cybrid) by repopulation of recipient rho(0) cells (devoid of mtDNA) with donor mtDNA derived from patients with breast cancer harboring the G10398A polymorphism. We investigated a number of functional phenotypes of the G10398A cybrid. The G10398A cybrid showed a slower proliferation rate and progression through the cell cycle, as well as increased complex I activity, increased levels of reactive oxygen species and depolarized mitochondria. The G10398A cybrid also showed resistance to apoptosis triggered by etoposide. Resistance to apoptosis was mediated by Akt activation. In addition, our studies showed that the G10398A cybrid cells form an increased number of anchorage-independent colonies in vitro and metastases in mice. Together our studies suggest that the G10398A variant confers resistance to apoptosis and promotes metastasis.
我们研究了在患有侵袭性乳腺癌的非裔美国女性中发现的线粒体 DNA（mtDNA）G10398A 多态性对细胞凋亡和肿瘤发生的影响。我们通过用源自携带有 G10398A 多态性的乳腺癌患者的供体 mtDNA 重新填充受体 rho(0) 细胞（缺乏 mtDNA）来生成人细胞质杂种（cybrid）。我们研究了 G10398A cybrid 的许多功能表型。G10398A cybrid 显示出较慢的增殖率和细胞周期进展，以及增加的复合物 I 活性、增加的活性氧水平和去极化的线粒体。G10398A cybrid 还显示出对依托泊苷触发的细胞凋亡的抗性。细胞凋亡的抗性是由 Akt 激活介导的。此外，我们的研究表明，G10398A cybrid 细胞在体外形成更多的无锚定依赖性集落和在小鼠中的转移。总之，我们的研究表明，G10398A 变体赋予细胞凋亡抗性并促进转移。
