Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant

Kwak, Eunice L.; Kim, Sang; Zhang, Jianmin; Cardiff, Robert D.; Schmidt, Emmett V.; Haber, Daniel A.

doi:10.1158/0008-5472.can-05-1237

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…The importance of the Chk2 kinase in cellular homeostasis is emphasized by the established link to its role as a tumor suppressor where certain and a very specific class of mutations lead to predisposition for various cancers (50). Chk2 null mice do not develop spontaneous tumors without additional genotoxic treatment, but the mice expressing the kinase-deficient version of Chk2 in mammary glands do develop mammary tumors spontaneously (51). The knock-in mouse with the human cancer predisposing Chk2*1100delC allele develops tumors with high frequency even without additionally induced genotoxic stress (52).…”

Section: Discussionmentioning

confidence: 99%

Checkpoint kinase 2 (Chk2) inhibits the activity of the Cdc45/MCM2-7/GINS (CMG) replicative helicase complex

Ilves

Tamberg

Botchan

2012

Proc. Natl. Acad. Sci. U.S.A.

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The replication of eukaryote chromosomes slows down when DNA is damaged and the proteins that work at the fork (the replisome) are known targets for the signaling pathways that mediate such responses critical for accurate genomic inheritance. However, the molecular mechanisms and details of how this response is mediated are poorly understood. In this report we show that the activity of replisome helicase, the Cdc45/MCM2-7/GINS (CMG) complex, can be inhibited by protein phosphorylation. Recombinant Drosophila melanogaster CMG can be stimulated by treatment with phosphatase whereas Chk2 but not Chk1 interferes with the helicase activity in vitro. The targets for Chk2 phosphorylation have been identified and reside in MCM subunits 3 and 4 and in the GINS protein Psf2. Interference requires a combination of modifications and we suggest that the formation of negative charges might create a surface on the helicase to allosterically affect its function. The treatment of developing fly embryos with ionizing radiation leads to hyperphosphorylation of Psf2 subunit in the active helicase complex. Taken together these data suggest that the direct modification of the CMG helicase by Chk2 is an important nexus for response to DNA damage.eukaryotic DNA replication | S-phase checkpoint response

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Section: Discussionmentioning

confidence: 99%

Checkpoint kinase 2 (Chk2) inhibits the activity of the Cdc45/MCM2-7/GINS (CMG) replicative helicase complex

Ilves

Tamberg

Botchan

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous investigations indicated that FVB females with prolactinomas and prolactin overstimulation of the mammary gland typically produce mammary adenosquamous carcinomas. 9,19,23 If true in all cohorts, prolactinrelated tumors could be readily identified and animals segregated. Importantly, these findings were not confirmed in this study.…”

Section: Discussionmentioning

confidence: 99%

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Radælli¹,

Arnold

Παπανικολάου

et al. 2009

Vet Pathol

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Abstract. Prolactin-secreting pituitary adenomas are common spontaneous lesions in aging FVB females. Prolactin-secreting pituitary proliferations play a significant role in mouse mammary tumorigenesis generally producing adenosquamous carcinomas. Since genetically engineered FVB mice are frequently used to study mammary tumor biology, we have examined a cohort of 64 aging wild-type FVB/N females to establish the prevalence and the nature of spontaneous mammary and pituitary tumors. Tissues from mammary and pituitary glands were studied by histopathology and immunohistochemistry. Of the 64 examined mice, 20 had pituitary tumors and 20 had mammary tumors. Mammary and pituitary tumors were associated in 17 mice. All pituitary tumors were prolactinpositive by immunohistochemistry and classified as prolactinomas. Fourteen mammary tumors, including 12 cases with and 2 without concurrent prolactinomas, were adenocarcinomas with different combinations of epithelial growth patterns. Five mice with prolactinomas had mammary tumors characterized by the epithelial-mesenchymal transition (EMT) phenotype. Estrogen receptor alpha (ERa)-positivity was observed for 14 of the 18 mammary tumors tested, including both adenocarcinomas with nuclear immunoreactivity and EMT-phenotype tumors with both nuclear and cytoplasmic immunoreactivity. No immunoreactivity for the progesterone receptor was observed. This study confirms that spontaneous prolactinomas and mammary tumors are both common and significantly associated lesions in FVB mice. Parity and age represented risk factors for the development of these tumors. Compared with previous reports, prolactinoma-associated mammary tumors displayed a broader morphologic spectrum, including cases with the EMT phenotype. The elevated number of prolactinoma-associated and ERa-positive mammary tumors opens intriguing possibilities concerning the role of ERa cytoplasmic localization during EMT tumorigenesis.

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“…Topical application of 7,12-dimethylbenz[a]anthracene (DMBA), however, accelerates the formation of skin tumors (29). In contrast, mice transgenic for a kinase-dead, dominant-negative Chk2 under control of a mouse mammary tumor virus (MMTV) promoter developed mammary tumors but only after a latency period of Ϸ20 months (30).…”

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confidence: 99%

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Bahassi

Robbins²,

Yin³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The CHEK2 kinase (Chk2 in mouse) is a member of a DNA damage response pathway that regulates cell cycle arrest at cell cycle checkpoints and facilitates the repair of dsDNA breaks by a recombination-mediated mechanism. There are numerous variants of the CHEK2 gene, at least one of which, CHEK2*1100delC (SNP), associates with breast cancer. A mouse model in which the wild-type Chk2 has been replaced by a Chk2*1100delC allele was tested for elevated risk of spontaneous cancer and increased sensitivity to challenge by a carcinogenic compound. Mice homozygous for Chk2*1100delC produced more tumors than wild-type mice, whereas heterozygous mice were not statistically different. When fractionated by gender, however, homozygous and heterozygous mice developed spontaneous tumors more rapidly and to a far greater extent than wild-type mice, indicative of a marked gender bias in mice harboring the variant allele. Consistent with our previous data showing elevated genomic instability in mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2*1100delC, the level of Cdc25A was elevated in heterozygous and homozygous MEFs and tumors. When challenged with the carcinogen 7,12-dimethylbenz[a]anthracene, all mice, regardless of genotype, had a reduced lifespan. Latency for mammary tumorigenesis was reduced significantly in mice homozygous for Chk2*1100delC but unexpectedly increased for the development of lymphomas. An implication from this study is that individuals who harbor the variant CHEK2*1100delC allele not only are at an elevated risk for the development of cancer but also that this risk can be further increased as a result of environmental exposure.cancer predisposition ͉ Cdc25A ͉ polymorphism

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Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant

Cited by 17 publications

References 30 publications

Checkpoint kinase 2 (Chk2) inhibits the activity of the Cdc45/MCM2-7/GINS (CMG) replicative helicase complex

Checkpoint kinase 2 (Chk2) inhibits the activity of the Cdc45/MCM2-7/GINS (CMG) replicative helicase complex

Mammary Tumor Phenotypes in Wild-Type Aging Female FVB/N Mice with Pituitary Prolactinomas

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

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