Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis
Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis
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DOI：
10.1101/gad.1565707
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发表时间：
2007-07-01
影响因子：
10.5
通讯作者：
White, Eileen
中科院分区：
文献类型：
--
作者：
Karantza-Wadsworth, Vassiliki;Patel, Shyam;White, Eileen
自噬是一种分解代谢过程，包括饥饿期间细胞器的自我消化，作为细胞生存的一种手段；然而，如果进行到完成，自噬可能会导致细胞死亡。自噬也是乳腺肿瘤发生的一种单倍体不足的肿瘤抑制机制，因为乳腺癌中基本的自噬调节因子Beclin1是单等位基因缺失的。然而，自噬抑制乳腺癌的机制仍然不清楚。在这里，我们展示了Beclin1的等位基因丢失和缺陷的自噬使乳腺上皮细胞对代谢应激敏感，并加速了乳腺腺泡的管腔形成。自噬缺陷还可以激活体外和体内乳腺肿瘤的DNA损伤反应，促进基因扩增，并与缺陷细胞凋亡协同作用，促进乳腺肿瘤的发生。因此，我们认为自噬限制代谢应激以保护基因组，而有缺陷的自噬增加DNA损伤和基因组不稳定性，最终促进乳腺癌的进展。
Autophagy is a catabolic process involving self-digestion of cellular organelles during starvation as a means of cell survival; however, if it proceeds to completion, autophagy can lead to cell death. Autophagy is also a haploinsufficient tumor suppressor mechanism for mammary tumorigenesis, as the essential autophagy regulator beclin1 is monoallelically deleted in breast carcinomas. However, the mechanism by which autophagy suppresses breast cancer remains elusive. Here we show that allelic loss of beclin1 and defective autophagy sensitized mammary epithelial cells to metabolic stress and accelerated lumen formation in mammary acini. Autophagy defects also activated the DNA damage response in vitro and in mammary tumors in vivo, promoted gene amplification, and synergized with defective apoptosis to promote mammary tumorigenesis. Therefore, we propose that autophagy limits metabolic stress to protect the genome, and that defective autophagy increases DNA damage and genomic instability that ultimately facilitate breast cancer progression.