Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability

Murata, Hiroaki; Khattar, Nada H.; Kang, Yuna; Gu, Liya; Li, Guo Min

doi:10.1038/sj.onc.1205683

Cited by 77 publications

(64 citation statements)

References 42 publications

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“…Whereas MSI in colorectal neoplasms is well characterized, data on breast cancer are still inconsistent with a reported MSI rate ranging from 0 to 50% (Paulson et al, 1996;Shaw et al, 1996;Anbazhagan et al, 1999;Murata et al, 2002). Such discrepancy could be linked to the histological type of tumors analysed or/and the number and sensitivity of the markers used.…”

Section: Cytogenetic Pattern Of Evolution and Tp53 And Msi Statusmentioning

confidence: 78%

Characterization of a new cytogenetic subtype of ductal breast carcinomas

et al. 2004

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About 50% of ductal breast carcinomas do not yield analysable karyotypes after short-term culturing. Comparison of the cytogenetic subset to the whole data set of tumors revealed that slightly hyperdiploid tumors, that is, with DNA index between 1.05 and 1.3, were underrepresented in tumors for which cytogenetic analysis was successful. The purpose of this study was to determine whether the pattern of chromosome imbalances in this subset differs from that generally reported. Comparative genomic hybridization (CGH) was used on 43 primary ductal breast carcinomas selected for slight hyperdiploidy. Microsatellite instability (MSI), TP53 mutation and expression were also investigated. All tumors were MSI negative. In all, 18 tumors (42%) presented mostly unbalanced chromosome rearrangements and DNA amplifications, with only few or no whole chromosome gains (WCG). This pattern of chromosome imbalances corresponds to that described in most breast tumors by previous cytogenetic and CGH analyses. It was associated with TP53 mutation in 17% of tumors. Another subset of 17 tumors (39%) displayed different and new features, characterized by recurrent gains of whole chromosomes 5, 7 and 8 with few chromosome rearrangements, rare DNA amplifications and no TP53 mutation. Eight tumors with as many rearrangements as WCG were left unclassified. We propose that, beside a major pathway characterized by multiple chromosome rearrangements, there is a minor pathway mainly characterized by WCG.

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Section: Cytogenetic Pattern Of Evolution and Tp53 And Msi Statusmentioning

confidence: 78%

Characterization of a new cytogenetic subtype of ductal breast carcinomas

et al. 2004

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“…The epigenetic effects of DNA methylation and their relationship to the transcriptional silencing of growth regulatory genes are important considerations in defining key processes in involved in tumorigenesis (63,64). Because epigenetic alteration of MMR genes contributes to genomic instability and tumorigenesis (65,66), epigenetic modification of MSH2 promoter might be another possible mechanism of MSH2 suppression in senescent cells.…”

Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

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“…PCR primers were designed to amplify 200-350 bp fragments of individual exons and exon-intron junctions of MSH2 and MLH1. These procedures were performed essentially as described previously [36]. PCR products were excised from SSCP gels, amplified by PCR, and sequenced.…”

Section: Mutation Detectionmentioning

confidence: 99%