Hypoxia-Induced Down-regulation of <i>BRCA1</i> Expression by E2Fs

Bindra, Ranjit S.; Gibson, Shannon L.; Meng, Alice; Westermark, Ulrica; Jasin, Maria; Pierce, Andrew J.; Bristow, Robert G.; Classon, Marie; Glazer, Peter M.

doi:10.1158/0008-5472.can-05-2119

Cited by 314 publications

(344 citation statements)

References 47 publications

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“…Moreover, since hypoxia decreases BRCA1 expression (Bindra et al, 2005), we further investigated the effects of normoxia and hypoxia on CYP1A1 and BRCA1 protein expression in ZR-75 cells (Figs. 5B and 5C).…”

Section: Results Inmentioning

confidence: 99%

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Khan

Liu

Stoner

et al. 2007

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-Erα crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1α or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFκB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 hr, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 hr, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 hr enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ahresponsiveness (under normoxia) that are also inhibited by cycloheximide.

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Section: Results Inmentioning

confidence: 99%

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Khan

Liu

Stoner

et al. 2007

Toxicology and Applied Pharmacology

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“…Hypoxic tumor cells exist in colorectal cancer, and the level of hypoxia is prognostic for clinical outcome (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Hypoxia may give rise to genetic instability by downregulating multiple DNA repair pathways, including the DNA mismatch repair (MMR) and homologous recombination (HR) pathways (20)(21)(22)(23)(24)(25)(26)(27). For example, Chan and colleagues demonstrated an alternate mechanism of translational inhibition of the HR proteins RAD51 and BRCA2 (23).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Provokes Base Excision Repair Changes and a Repair-Deficient, Mutator Phenotype in Colorectal Cancer Cells

Chan

Ali

McCallum

et al. 2014

Molecular Cancer Research

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Regions of acute and chronic hypoxia exist within solid tumors and can lead to increased rates of mutagenesis and/ or altered DNA damage and repair protein expression. Base excision repair (BER) is responsible for resolving small, non-helix-distorting lesions from the genome that potentially cause mutations by mispairing or promoting DNA breaks during replication. Germline and somatic mutations in BER genes, such as MutY Homolog (MUTYH/ MYH) and DNA-directed polymerase (POLB), are associated with increased risk of colorectal cancer. However, very little is known about the expression and function of BER proteins under hypoxic stress. Using conditions of chronic hypoxia, decreased expression of BER proteins was observed because of a mechanism involving suppressed BER protein synthesis in multiple colorectal cancer cell lines. Functional BER was impaired as determined by MYH-and 8-oxoguanine (OGG1)-specific glycosylase assays. A formamidopyrimidine-DNA glycosylase (Fpg) Comet assay revealed elevated residual DNA base damage in hypoxic cells 24 hours after H 2 O 2 treatment as compared with normoxic controls. Similarly, high-performance liquid chromatography analysis demonstrated that 8-oxo-2 0 -deoxyguanosine lesions were elevated in hypoxic cells 3 and 24 hours after potassium bromate (KBrO 3 ) treatment when compared with aerobic cells. Correspondingly, decreased clonogenic survival was observed following exposure to the DNA base damaging agents H 2 O 2 and MMS, but not to the microtubule interfering agent paclitaxel. Thus, a persistent downregulation of BER components by the microenvironment modifies and facilitates a mutator phenotype, driving genetic instability and cancer progression.

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“…A model of acute hypoxia-induced transcriptional repression has been proposed by Bindra et al (23,26) who showed that the hypoxic down-regulation of RAD51 and BRCA1 can be mediated by altered E2F transcriptional activation and repression. In other cell lines, the RNA and protein expression of HR genes is discordant after chronic hypoxic exposure (25), suggesting an additional level of genetic control.…”

Section: Introductionmentioning

confidence: 99%

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

et al. 2008

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Hypoxic and/or anoxic tumor cells can have increased rates of mutagenesis and altered DNA repair protein expression. Yet very little is known regarding the functional consequences of any hypoxia-induced changes in the expression of proteins involved in DNA double-strand break repair. We have developed a unique hypoxic model system using H1299 cells expressing an integrated direct repeat green fluorescent protein (DR-GFP) homologous recombination (HR) reporter system to study HR under prolonged chronic hypoxia (up to 72 h under 0.2% O 2 ) without bias from altered proliferation, cell cycle checkpoint activation, or severe cell toxicity. We observed decreased expression of HR proteins due to a novel mechanism involving decreased HR protein synthesis. Error-free HR was suppressed 3-fold under 0.2% O 2 as measured by the DR-GFP reporter system. This decrease in functional HR resulted in increased sensitivity to the DNA cross-linking agents mitomycin C and cisplatin but not to the microtubule-interfering agent, paclitaxel. Chronically hypoxic H1299 cells that had decreased functional HR were relatively radiosensitive [oxygen enhancement ratio (OER), 1.37] when compared with acutely hypoxic or anoxic cells (OER, 1.96-2.61). Using CAPAN1 cells isogenic for BRCA2 and siRNA to RAD51, we confirmed that the hypoxia-induced radiosensitivity was due to decreased HR capacity. Persistent down-regulation of HR function by the tumor microenvironment could result in low-fidelity DNA repair and have significant implications for response to therapy and genetic instability in human cancers. [Cancer Res 2008;68(2):605-14]

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Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs

Cited by 314 publications

References 47 publications

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

Hypoxia Provokes Base Excision Repair Changes and a Repair-Deficient, Mutator Phenotype in Colorectal Cancer Cells

Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance

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