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RAP80 is critical in maintaining genomic stability and suppressing tumor development.

ABSTRACT: The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80(-/-)) mice. RAP80(-/-) mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEF) derived from RAP80(-/-) mice underwent premature senescence compared with wild-type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80(-/-) thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80(-/-) mice were more susceptible to spontaneous lymphoma development and the development of 7,12-dimethylbenz(a)anthracene-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53(-/-) and p53(+/-) mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function.

SUBMITTER: Yin Z

PROVIDER: S-EPMC3482830 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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RAP80 is critical in maintaining genomic stability and suppressing tumor development.

Yin Zhengyu Z Menendez Daniel D Resnick Michael A MA French John E JE Janardhan Kyathanahalli S KS Jetten Anton M AM

Cancer research 20120815 19

The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80(-/-)) mice. RAP80(-/-) mice are viable and did not exhibit any apparent developmental defects. Mouse ...[more]

PMID: 22896338

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Project description:The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations, including epigenetic modifications to DNA, and changes in RNA and protein expression have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations in the breast stroma is a reflection of technological artifact rather than the true genomic content of the tumor microenvironment. Methods: Surgically-removed breast stroma specimens from 112 women undergoing reductive mammoplasty (n=15), prophylactic mastectomy (N=6) or mastectomy for a diagnosis of breast disease (n=92) were frozen in optimal cutting temperature medium. Allelic imbalance (AI) analysis was performed in 484 stromal specimens from 98 women using a panel of 52 microsatellite markers; SNP data was generated from a subset of 86 stromal specimens using 250K SNP arrays (Affymetrix). Copy number alterations were identified using Partek Genomics Suite. Results: AI was not detected in 92% (444/484) of stroma specimens. When compared to previously generated AI data from 77 formalin-fixed, paraffin-embedded stroma specimens (Ellsworth et al., Ann Surg Oncol 2004), 32 (42%) of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P<0.0001) than that found in frozen specimens (0.45%). Of the stroma specimens assayed using SNP arrays 95% (82/86) had no detectable alterations and the 11 copy number changes were small and not shared between specimens. Conclusions: The data presented here support a model in which the tumor microenvironment is genetically stable. The direct comparison of copy number alterations between FFPE and frozen research-grade specimens using identical methodologies suggests that past reports of significant AI in breast stroma, both adjacent to and distant from the tumor, reflects artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage. 250K STY data was generated for 86 breast stromal specimens. The tissue specimens were analyzed by paired analysis to the SNP data from matched genomic (blood) DNAs

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RAP80 is critical in maintaining genomic stability and suppressing tumor development.

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RAP80 is critical in maintaining genomic stability and suppressing tumor development.

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