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Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53

Oncogene volume 29, pages 4007–4017 (2010)Cite this article

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Abstract

Checkpoint kinase 1 (Chk1) is a key element in the DNA-damage response pathway that is required for maintaining genomic stability. To study the potential role of Chk1 in mammary tumorigenesis, we disrupted it using a Cre/loxP system. We showed that although Chk1 heterozygosity caused abnormal development of the mammary gland, it was not sufficient to induce tumorigenesis. Simultaneous deletion of one copy of p53 failed to rescue the developmental defects; however, it synergistically induced mammary tumor formation in Chk1+/−;MMTV-Cre animals with a median time to tumor latency of about 10 months. Chk1 deficiency caused a preponderance of abnormalities, including prolongation, multipolarity, misalignment, mitotic catastrophe and loss of spindle checkpoint, that are accompanied by reduced expression of several cell cycle regulators, including Mad2. On the other hand, we also showed that Chk1 deficiency inhibited mammary tumor formation in mice carrying a homozygous deletion of p53, uncovering a complex relationship between Chk1 and p53. Furthermore, inhibition of Chk1 with a specific inhibitor, SB-218078, or acute deletion of Chk1 using small hairpin RNA killed mammary tumor cells effectively. These data show that Chk1 is critical for maintaining genome integrity and serves as a double-edged sword for cancer: although its inhibition kills cancer cells, it also triggers tumorigenesis when favorable mutations are accumulated for cell growth.

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Acknowledgements

We gratefully acknowledge members of Deng laboratory for a critical reading of the article. This work was supported by the Intramural Research Program of the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, USA.

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  1. T Fishler and Y-Y Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, USA

    T Fishler, Y-Y Li, R-H Wang, H-S Kim, A Vassilopoulos, T Lahusen, X Xu, M-H Lee & C-X Deng

  2. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    K Sengupta & T Ried

  3. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Q Liu & S-J Elledge

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Correspondence to C-X Deng.

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Fishler, T., Li, YY., Wang, RH. et al. Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53. Oncogene 29, 4007–4017 (2010). https://doi.org/10.1038/onc.2010.163

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