TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage

Dubrovska, Anna; Kanamoto, Takashi; Lomnytska, Marta; Heldin, Carl‐Henrik; Volodko, Natalya; Souchelnytskyi, Serhiy

doi:10.1038/sj.onc.1208443

Cited by 57 publications

(47 citation statements)

References 30 publications

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“…Additionally, increased TGF-β1/Smad3 in HN-Smad4 -/-tissues could contribute to downregulation of the Fanc/Brca pathway. In support of the latter hypothesis, Smad3 has been shown to bind to the Brca1 protein and inhibit Brca1 nuclear foci formation and DNA repair efficiency (49). Thus, genomic instability coupled with hyperproliferation and reduced apoptosis may allow HN-Smad4 -/-cells to escape from DNA damage-induced cell death during tumorigenesis.…”

Section: Figurementioning

confidence: 68%

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

et al. 2009

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Smad4 is a central mediator of TGF-β signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4 -/-mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4 -/-mice exhibited severe inflammation, which was associated with increased expression of TGF-β1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

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Section: Figurementioning

confidence: 68%

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

et al. 2009

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“…Although these data refer to a situation without irradiation, they might be comparable to our 16-h TGF-b1 preincubation. In addition, it has been shown that TGF-b1 via SMAD3 counteracts BRCA1-dependent DNA repair (35), thus supporting an effect of TGF-b1 impairing DNA integrity. However, several days after irradiation, reduced numbers of cells harboring chromosomal aberrations were noticed in the presence of TGF-b1 (14).…”

Section: Discussionmentioning

confidence: 97%

A Putatively Functional Haplotype in the Gene Encoding Transforming Growth Factor Beta-1 as a Potential Biomarker for Radiosensitivity

Schirmer

Brockmöller

Rave-Fränk

et al. 2011

International Journal of Radiation Oncology*Biology*Physics

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“…However, it is unclear at this stage as to the functional role of the BRCA1 and/or BRCA2 associated irradiation [29][30][31], suggesting an alternative mode of activity for many of the candidate modifier genes.…”

Section: Discussionmentioning

confidence: 97%

Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers

Walker¹,

Waddell²,

Haaf³

et al. 2007

Breast Cancer Res Treat

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Germline mutations in BRCA1 or BRCA2 confer an increased lifetime risk of developing breast or ovarian cancer, but variable penetrance suggests that cancer susceptibility is influenced in part by modifier genes. Microarray expression profiling was conducted for 69 irradiated lymphoblastoid cell lines derived from healthy controls, or from cancer-affected women with a strong family history of breast and ovarian cancer carrying pathogenic mutations in BRCA1 or BRCA2, or with no BRCA1/2 mutations (BRCAX). Genes discriminating between BRCA1, BRCA2 or BRCAX and controls were stratified based on irradiation response and/or cell cycle involvement. Gene lists were aligned against genes tagged with single nucleotide polymorphisms (SNPs) determined by the Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Whole Genome Association Scan to be nominally associated with breast cancer risk. Irradiation responsive genes whose expression correlated with BRCA1 and/or BRCA2 mutation status were more likely to be tagged by risk-associated SNPs in the CGEMS dataset (BRCA1, P = 0.0005; BRCA2, P = 0.01). In contrast, irradiation responsive genes correlating with BRCAX status were not enriched in the CGEMS dataset. Classification of expression data by involvement in cell cycle processes did not enrich for genes tagged by risk-associated SNPs, for BRCA1, BRCA2 or BRCAX groups. Using a novel combinatorial approach, we have identified a subset of irradiation responsive genes as high priority candidate BRCA1/2 modifier genes. Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved.

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TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage

Cited by 57 publications

References 30 publications

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation

A Putatively Functional Haplotype in the Gene Encoding Transforming Growth Factor Beta-1 as a Potential Biomarker for Radiosensitivity

Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers

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