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不充分的DNA损伤修复促进乳腺转化,导致BRCA1乳腺癌

Hua Wang¹, Dongxi Xiang², Ben Liu¹

¹Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Genetics and Medicine, Harvard Medical School, Boston, MA 02115, USA.

|June 29, 2019

概括

由于导致DNA损伤和细胞转化,BRCA1功能丧失导致基底性乳腺癌. 这项研究揭示了未修复的DNA损伤如何驱动乳腺上皮细胞 (MEC) 的恶性转变.

科学领域:

癌症学
分子生物学
遗传学

背景情况:

BRCA1 p220功能的丧失与基底类乳腺癌 (BLBC) 有关,但机制尚不清楚.
在乳腺上皮细胞 (MEC) 中,BRCA1与NUMB和HES1合作进行DNA修复和分化控制.
未修复的DNA损伤可以诱导MEC转化为介质细胞状态.

研究的目的:

阐明BRCA1损失导致基底类乳腺癌的机制.
研究DNA损伤和转基因差异化在BRCA1缺陷乳腺癌发展中的作用.
了解BRCA1相关BLBC中从正常MEC转变为瘤细胞的细胞进化过程.

主要方法:

研究了乳腺上皮细胞 (MEC) 中的BRCA1,NUMB和HES1的功能.
在小鼠MEC中使用化学诱导的跨链损伤 (ICL).
在体内进行单细胞分析以追踪瘤发育过程中的细胞进化.

主要成果:

在小鼠MEC中,BRCA1,NUMB或HES1的损失或诱导的ICL损伤会导致持续的DNA损伤和光线转移到基底/介质.
在体内单细胞分析显示,在BRCA1BLBC发育过程中,从正常的光线MEC向基底/介质瘤细胞的进展取决于时间.
在BRCA1缺乏的小鼠模型中,增加的DNA损伤与恶性转变相关.

结论:

持续的DNA损伤和随后的转基因差异化是BRCA1相关的基础性乳腺癌的关键机制.
在MEC中,BRCA1在维持基因组稳定性和正常细胞分化方面发挥着关键作用.
了解这些途径为BLBC治疗提供了潜在的目标.

关键词:

其他:国际货币基金组织一个EMT 其他类型在ICL修复其他国家乳腺癌细胞命运西斯普拉丁鼠标模型单细胞分析转变差异化

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