Brca1-Deficient Murine Mammary Epithelial Cells have Increased Sensitivity to CDDP and MMS

Sgagias, Magdalene K.; Wagner, Kay Uwe; Hamik, Brad; Stoeger, Scott M.; Spieker, Rebecca; Huber, Lysiane; Chodosh, Lewis A.; Cowan, Kenneth H.

doi:10.4161/cc.3.11.1211

Cited by 40 publications

(34 citation statements)

References 43 publications

(49 reference statements)

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“…Several in vitro studies show the relevance of the integrity of the BRCA1 pathway for tumor response to chemotherapy. It has been shown that BRCA1 deficiency is linked to sensitivity to cisplatin and other DNA damaging agents (44,45), although the need for further clinical studies of BRCA1 and response to chemotherapy has recently been highlighted (46). The current study is a retrospective study of a group of patients that have not all had the same chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer

Teodoridis

Hall²,

Marsh³

et al. 2005

Cancer Research

222

147

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We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, <10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position À149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation. (Cancer Res 2005; 65(19): 8961-7)

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Section: Discussionmentioning

confidence: 99%

CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer

Teodoridis

Hall²,

Marsh³

et al. 2005

Cancer Research

222

147

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“…The analysis of these BRCA1-defective models has suggested an increased sensitivity to specific categories of chemotherapeutic agents. In particular, BRCA1 deficiency seems to sensitize cells to alkylating agents that induce intrastrand and interstrand cross-links (ICL), phenomenon that has been associated to the role played by BRCA1 in homologous recombination (14,19), whereas contradictory results have been instead obtained with other chemotherapeutics such as the topoisomerase II inhibitors (15,16,19). The molecular bases of this characteristic response and how the increased susceptibility of BRCA1-defective tumor cells to ICL inducers may be exploited to improve the treatment of BRCA1 patients still require investigations.…”

Section: Introductionmentioning

confidence: 99%

“…Most of our knowledge on the role of BRCA1 in the drug response of breast cancer cells comes from studies done on murine cell models or on a breast cancer cell line (HCC1937) obtained from a carrier of BRCA1 mutation (14)(15)(16)(17)(18)(19). The analysis of these BRCA1-defective models has suggested an increased sensitivity to specific categories of chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

Santarosa

Col

Tonin

et al. 2009

Molecular Cancer Therapeutics

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BRCA1-associated tumors are characterized by an elevated genomic instability and peculiar expression profiles. Nevertheless, tailored treatments for BRCA1 mutation carriers have only been partially investigated up to now. The implementation of therapeutic strategies specific for these patients has been in part hindered by the paucity of proper preneoplastic and neoplastic BRCA1-deficient tumor cell models. In this study, we took advantage of the RNA interference technology to generate a series of partially transformed (HBL100) and tumorigenic (MCF7 and T47D) breast cancer cell lines in which BRCA1 expression was silenced at different levels. These cell models were probed by clonogenic assay for their response to several DNA-damaging agents commonly used in cancer therapy (mitomycin C, cisplatin, doxorubicin, and etoposide). Our models confirmed the peculiar sensitivity to interstrand cross-link inducers associated with BRCA1 deficiency. Intriguingly, the increased sensitivity to these compounds displayed by BRCA1-defective cells was not correlated with the extent of apoptotic cell death but rather associated to an increased fraction of growth-arrested, enlarged, multinucleated β-galactosidase-positive senescent cells. Overall, our results support a role for BRCA1 in the regulation of interstrand cross-link-induced premature senescence and suggest a reconsideration of the therapeutic power of mitomycin/platinum-based treatments in BRCA1 carriers. Moreover, our data further prompt the setup of strategies for the imaging of the senescence response in vivo.

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“…BRCA1 defective cells show significant sensitivity to the DNA cross-linking agent mitomycin C, which is a hallmark of defective HR. 16,53 Indeed, HR defects confer sensitivity to a wide range of DNA cross linking agents. 54 HR can be measured directly using a plasmid based artificial DNA recombination substrate integrated into the genome.…”

Section: Introductionmentioning

confidence: 99%

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

Durant¹,

Nickoloff²

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2027 KEY WORDSBRCA1, NHEJ, HR, MRE11, RAD50, NBS1, exonuclease, cell cycle, DSB repair ABBREVIATIONS NHEJ non-homologous end-joining HR homologous recombination DSB double-strand break ACKNOWLEDGEMENTSOur research on the NHEJ/HR interface is supported by grant CA100862 from the National Cancer Institute, NIH. ReviewGood Timing in the Cell Cycle for Precise DNA Repair by BRCA1 ABSTRACTIt is now clear that large DNA-binding proteins have evolved in mammals to orchestrate the relatively ancient process of DNA recombinational repair. These proteins are recruited to accurately repair DNA double strand breaks (DSBs)-the frequent, potentially lethal and mutagenic lesions in the genomes of all organisms. An essential mammalian regulator of DSB repair is BRCA1. Heterozygous BRCA1 mutations predispose individuals to breast, ovarian and other secondary cancers. BRCA1-defective cells exhibit reduced DSB repair, sensitivity to a wide range of DNA damaging agents, genomic instability and defects in the S-phase checkpoint, transcription and chromatin remodelling. DSBs can be repaired by RAD51/RPA-dependent homologous recombination (HR) or DNA-PK-dependent nonhomologous end-joining (NHEJ). Both of these pathways can be imprecise and mutagenic. BRCA1 plays a central role in promoting accurate repair by both HR and NHEJ. Consistent with recent evidence, we have assembled a novel cell-cycle-dependent model in which DNA-PK inhibits RPA in S-phase of the cell cycle, while BRCA1 inhibits the exonuclease processivity of the MRE11/RAD50/NBS1 (MRN) complex and facilitates the removal of RPA in S and G 2 phase. This model provides an explanation for how BRCA1 promotes accurate DSB repair during various phases of the cell cycle and also accounts for the dual effects that BRCA1 and MRN activity have upon DNA repair and S-phase arrest.

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Brca1-Deficient Murine Mammary Epithelial Cells have Increased Sensitivity to CDDP and MMS

Cited by 40 publications

References 43 publications

CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer

CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

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