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PTEN 和 ATM 轴控制 HER2 阳性乳腺癌中的 G1/S 细胞周期检查点和肿瘤发生。

The PTEN and ATM axis controls the G1/S cell cycle checkpoint and tumorigenesis in HER2-positive breast cancer.

机构信息

Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, ON, M5G 2C1, Canada.

Epigenetics and Genome Stability Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

出版信息

Cell Death Differ. 2021 Nov;28(11):3036-3051. doi: 10.1038/s41418-021-00799-8. Epub 2021 May 31.

DOI:10.1038/s41418-021-00799-8
PMID:34059798
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8564521/
Abstract

The tumor suppressor PTEN is disrupted in a large proportion of cancers, including in HER2-positive breast cancer, where its loss is associated with resistance to therapy. Upon genotoxic stress, ataxia telangiectasia mutated (ATM) is activated and phosphorylates PTEN on residue 398. To elucidate the physiological role of this molecular event, we generated and analyzed knock-in mice expressing a mutant form of PTEN that cannot be phosphorylated by ATM (PTEN-398A). This mutation accelerated tumorigenesis in a model of HER2-positive breast cancer. Mammary tumors in bi-transgenic mice carrying MMTV-neu and Pten were characterized by DNA damage accumulation but reduced apoptosis. Mechanistically, phosphorylation of PTEN at position 398 is essential for the proper activation of the S phase checkpoint controlled by the PI3K-p27-CDK2 axis. Moreover, we linked these defects to the impaired ability of the PTEN-398A protein to relocalize to the plasma membrane in response to genotoxic stress. Altogether, our results uncover a novel role for ATM-dependent PTEN phosphorylation in the control of genomic stability, cell cycle progression, and tumorigenesis.

摘要

抑癌基因 PTEN 在包括 HER2 阳性乳腺癌在内的大量癌症中发生了缺失，其缺失与治疗耐药有关。在遗传毒性应激下，共济失调毛细血管扩张突变蛋白（ATM）被激活并使 PTEN 的第 398 位残基磷酸化。为了阐明这一分子事件的生理作用，我们构建并分析了表达一种不能被 ATM 磷酸化的 PTEN 突变体（PTEN-398A）的敲入小鼠。这种突变加速了 HER2 阳性乳腺癌模型中的肿瘤发生。携带 MMTV-neu 和 Pten 的双转基因小鼠的乳腺肿瘤表现出 DNA 损伤积累，但凋亡减少。从机制上讲，PTEN 在第 398 位的磷酸化对于由 PI3K-p27-CDK2 轴控制的 S 期检查点的适当激活是必需的。此外，我们将这些缺陷与 PTEN-398A 蛋白在应对遗传毒性应激时不能重新定位到质膜的能力受损联系起来。总之，我们的研究结果揭示了 ATM 依赖性 PTEN 磷酸化在控制基因组稳定性、细胞周期进程和肿瘤发生中的新作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/bd60ac7536e4/41418_2021_799_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/0a9653f53ecb/41418_2021_799_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/84b4c51d5e33/41418_2021_799_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/57be1538b3f7/41418_2021_799_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/2c69967d7bf2/41418_2021_799_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/e27481796d35/41418_2021_799_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/bd60ac7536e4/41418_2021_799_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/0a9653f53ecb/41418_2021_799_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/84b4c51d5e33/41418_2021_799_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/57be1538b3f7/41418_2021_799_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/2c69967d7bf2/41418_2021_799_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/e27481796d35/41418_2021_799_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6298/8564521/bd60ac7536e4/41418_2021_799_Fig6_HTML.jpg

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