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Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53
- Source :
- Oncogene
- Publication Year :
- 2010
- Publisher :
- Springer Science and Business Media LLC, 2010.
-
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.
- Subjects :
- Cancer Research
medicine.medical_specialty
animal structures
Mad2
Tumor suppressor gene
Biology
medicine.disease_cause
environment and public health
Genomic Instability
Article
Mice
Internal medicine
Genetics
medicine
Animals
CHEK1
Molecular Biology
Mitotic catastrophe
DNA Primers
Mice, Knockout
Mammary tumor
Base Sequence
Reverse Transcriptase Polymerase Chain Reaction
Spectral Karyotyping
Mammary Neoplasms, Experimental
Cell cycle
enzymes and coenzymes (carbohydrates)
Spindle checkpoint
Endocrinology
Checkpoint Kinase 1
Cancer research
Tumor Suppressor Protein p53
biological phenomena, cell phenomena, and immunity
Carcinogenesis
Protein Kinases
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....38c0fd1d4ff87c1c5149f9aa29aa2836