DNA Repair Gene Expression and Risk of Locoregional Relapse in Breast Cancer Patients

Scodan, Romuald Le; Cizeron-Clairac, Géraldine; Fourme, Emmanuelle; Meseure, Didier; Vacher, Sophie; Spyratos, Frédérique; Lande, B. De La; Cvitkovic, F.; Lidereau, Rosette; Bièche, Ivan

doi:10.1016/j.ijrobp.2009.07.1735

Cited by 29 publications

(29 citation statements)

References 45 publications

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“…Interestingly, in addition, we found that key HR genes such as Rad51 were significantly enriched upon Ezh2 depletion in mouse glioblastoma and seven human GBM cell lines. Consistent with data in several other tumor types (Qiao et al, 2005;Le Scodan et al, 2010), elevated RAD51 protein levels in glioblastoma are correlated with worse outcome and resistance to DNA damage by stimulating HR (Vispé et al, 1998). Decreased RAD51 levels result in increased sensitivity to radiation and chemotherapeutic drugs in glioma cells (Bao et al, 2006;Quiros et al, 2011).…”

Section: Discussionsupporting

confidence: 76%

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

et al. 2015

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EZH2 is frequently overexpressed in glioblastoma (GBM), suggesting an oncogenic function that could be a target for therapeutic intervention. However, reduced EZH2 activity can also promote tumorigenesis, leading to concerns about the use of EZH2 inhibitors. Here, we provide further insight about the effects of prolonged Ezh2 inhibition in glioblastoma using preclinical mouse models and primary tumor-derived human GBM cell lines. Using doxycycline-inducible shRNAs that mimic the effects of a selective EZH2 inhibitor, we demonstrate that prolonged Ezh2 depletion causes a robust switch in cell fate, including significantly enhanced proliferation, DNA damage repair, and activation of part of the pluripotency network, resulting in altered tumor cell identity and tumor progression. Short-term Ezh2 depletion significantly improved survival without the tumor progression observed upon prolonged Ezh2 depletion, suggesting that precise dosing regiments are very important. These results could be of high clinical relevance with regard to how glioblastomas should be treated with epigenetic therapies.

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Section: Discussionsupporting

confidence: 76%

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

et al. 2015

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“…RAD51 plays a central role in DNA repair by forming a complex with BRCA2 , but its overexpression in breast cancer has been found to be associated with poor prognosis. [58, 59] In breast cancer cell lines, overexpression of RAD51 has been shown to drive genomic instability and tumorigenesis as excess RAD51 actually hampers the ability of cells to repair DNA. [60] Given RAD51 ’s oncogenic role, the targeting of RAD5 1 as a cancer therapy is currently being explored for difficult-to-treat cancers such as triple negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

et al. 2016

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Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs—hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p —each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.

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“…For example, it has been shown that acquired resistance to Pt accounted for treatment failure and deaths in up to 90% of patients with ovarian cancer [12]. Moreover, it has been demonstrated that increased Rad51 expression, evident of HR, is associated with poor treatment outcomes in breast cancer patients [13]. …”

Section: Introductionmentioning

confidence: 99%

Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

et al. 2014

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Chemotherapeutic anticancer drugs mediate cytotoxicity by a number of mechanisms. However, alkylating agents which induce DNA interstrand crosslinks (ICL) are amongst the most effective anticancer agents and often form the mainstay of many anticancer therapies. The effectiveness of these drugs can be limited by the development of drug resistance in cancer cells and many studies have demonstrated that alterations in DNA repair kinetics are responsible for drug resistance. In this study we developed two cell lines resistant to the alkylating agents nitrogen mustard (HN2) and cisplatin (Pt). To determine if drug resistance was associated with enhanced ICL DNA repair we used immunocytochemistry and imaging flow cytometry to quantitate the number of γ-H2AX and Rad51 foci in the nuclei of cells after drug exposure. γ-H2AX was used to evaluate DNA strand breaks caused by repair incision nucleases and Rad51 was used to measure the activity of homologous recombination in the repair of ICL. In the drug-resistant derivative cell lines there was overall a significant increase in the number and persistence of both γ-H2AX and Rad51 foci in the nuclei of cells over a 72-hour period, when compared to the non-resistant parental cell lines (ANOVA p < 0.0001). In a Pt-resistant ovarian cancer cell line (A2780cis^R) a similar enhancement of DNA repair was observed when compared to the non-drug-resistant wild-type ovarian cancer cells (A2780) following exposure to HN2. Our data suggest that using DNA repair biomarkers to evaluate mechanisms of resistance in cancer cell lines and human tumours may be of experimental and clinical benefit. We concede, however, that examination of a larger population of cell lines and tumours is required to fully evaluate the validity of this approach.

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DNA Repair Gene Expression and Risk of Locoregional Relapse in Breast Cancer Patients

Cited by 29 publications

References 45 publications

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

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DNA Repair Gene Expression and Risk of Locoregional Relapse in Breast Cancer Patients

Cited by 29 publications

References 45 publications

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

Prolonged Ezh2 Depletion in Glioblastoma Causes a Robust Switch in Cell Fate Resulting in Tumor Progression

Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

Increased &#947;-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin

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Increased γ-H2AX and Rad51 DNA Repair Biomarker Expression in Human Cell Lines Resistant to the Chemotherapeutic Agents Nitrogen Mustard and Cisplatin