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  • American Association for Cancer Research (AACR)  (10)
  • 1
    Online-Ressource
    Online-Ressource
    The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 20 ( 2014-10-15), p. 5808-5818
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 20 ( 2014-10-15), p. 5808-5818
    Kurzfassung: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-1531
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2014
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 7 ( 2013-04-01), p. 2211-2220
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 7 ( 2013-04-01), p. 2211-2220
    Kurzfassung: Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene–environment interactions, most notably NAT2 (P = 7 × 10−4) and UGT1A6 (P = 8 × 10−4). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10−4). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211–20. ©2012 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-2388
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2013
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 19, No. 12 ( 2010-12-01), p. 3140-3149
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 12 ( 2010-12-01), p. 3140-3149
    Kurzfassung: Background: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A1 versus A2 variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A1 allele would confer greater risk than A2 allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. Methods: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. Results: An increased risk was observed in participants with A1 but not A2 alleles. Compared with subjects with genotype O/O, genotypes A2/O, A2/A1, A1/O, and A1/A1 had ORs of 0.96 (95% CI, 0.72–1.26), 1.46 (95% CI, 0.98–2.17), 1.48 (95% CI, 1.23–1.78), and 1.71 (95% CI, 1.18–2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A1, and A2 were 1.00 (95% CI, 0.87–1.14), 1.38 (95% CI, 1.20–1.58), and 0.96 (95% CI, 0.77–1.20); P, O01 versus O02 = 0.94, A1 versus A2 = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). Conclusions: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. Impact: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34. Cancer Epidemiol Biomarkers Prev; 19(12); 3140–9. ©2010 AACR.
    Materialart: Online-Ressource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-10-0751
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2010
    ZDB Id: 2036781-8
    ZDB Id: 1153420-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 3 ( 2010-02-01), p. 1015-1023
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 3 ( 2010-02-01), p. 1015-1023
    Kurzfassung: A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18–1.62], 1.47 (95% CI, 1.07–2.02), and 1.53 (95% CI, 1.21–1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13–1.58) and 1.61 (95% CI, 1.22–2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14–1.85) and 2.42 (1.28–4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03–3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk. Cancer Res; 70(3); 1015–23
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-2993
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2010
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    Height, Body Mass Index, and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 17, No. 4 ( 2008-04-01), p. 902-912
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 17, No. 4 ( 2008-04-01), p. 902-912
    Kurzfassung: Background: Although many studies have investigated the association between anthropometry and ovarian cancer risk, results have been inconsistent. Methods: The associations of height, body mass index (BMI), and ovarian cancer risk were examined in a pooled analysis of primary data from 12 prospective cohort studies from North America and Europe. The study population consisted of 531,583 women among whom 2,036 epithelial ovarian cancer cases were identified. To summarize associations, study-specific relative risks (RR) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Results: Women with height ≥1.70 m had a pooled multivariate RR of 1.38 [95% confidence interval (95% CI), 1.16-1.65] compared with those with height & lt;1.60 m. For the same comparison, multivariate RRs were 1.79 (95% CI, 1.07-3.00) for premenopausal and 1.25 (95% CI, 1.04-1.49) for postmenopausal ovarian cancer (Pinteraction = 0.14). The multivariate RR for women with a BMI ≥30 kg/m2 was 1.03 (95% CI, 0.86-1.22) compared with women with a BMI from 18.5 to 23 kg/m2. For the same comparison, multivariate RRs were 1.72 (95% CI, 1.02-2.89) for premenopausal and 1.07 (95% CI, 0.87-1.33) for postmenopausal women (Pinteraction = 0.07). There was no statistically significant heterogeneity between studies with respect to height or BMI. BMI in early adulthood was not associated with ovarian cancer risk. Conclusion: Height was associated with an increased ovarian cancer risk, especially in premenopausal women. BMI was not associated with ovarian cancer risk in postmenopausal women but was positively associated with risk in premenopausal women. (Cancer Epidemiol Biomarkers Prev 2008;17(4):902–12)
    Materialart: Online-Ressource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-07-2524
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2008
    ZDB Id: 2036781-8
    ZDB Id: 1153420-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Online-Ressource
    Online-Ressource
    Dairy Products and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 15, No. 2 ( 2006-02-01), p. 364-372
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 15, No. 2 ( 2006-02-01), p. 364-372
    Kurzfassung: Background: Dairy foods and their constituents (lactose and calcium) have been hypothesized to promote ovarian carcinogenesis. Although case-control studies have reported conflicting results for dairy foods and lactose, several cohort studies have shown positive associations between skim milk, lactose, and ovarian cancer. Methods: A pooled analysis of the primary data from 12 prospective cohort studies was conducted. The study population consisted of 553,217 women among whom 2,132 epithelial ovarian cases were identified. Study-specific relative risks and 95% confidence intervals were calculated by Cox proportional hazards models and then pooled by a random-effects model. Results: No statistically significant associations were observed between intakes of milk, cheese, yogurt, ice cream, and dietary and total calcium intake and risk of ovarian cancer. Higher lactose intakes comparing ≥30 versus & lt;10 g/d were associated with a statistically significant higher risk of ovarian cancer, although the trend was not statistically significant (pooled multivariate relative risk, 1.19; 95% confidence interval, 1.01-1.40; Ptrend = 0.19). Associations for endometrioid, mucinous, and serous ovarian cancer were similar to the overall findings. Discussion: Overall, no associations were observed for intakes of specific dairy foods or calcium and ovarian cancer risk. A modest elevation in the risk of ovarian cancer was seen for lactose intake at the level that was equivalent to three or more servings of milk per day. Because a new dietary guideline recommends two to three servings of dairy products per day, the relation between dairy product consumption and ovarian cancer risk at these consumption levels deserves further examination. (Cancer Epidemiol Biomarkers Prev 2006;15(2):364–72)
    Materialart: Online-Ressource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-05-0484
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2006
    ZDB Id: 2036781-8
    ZDB Id: 1153420-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
    Online-Ressource
    Fruits and Vegetables and Ovarian Cancer Risk in a Pooled Analysis of 12 Cohort Studies
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 14, No. 9 ( 2005-09-01), p. 2160-2167
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 14, No. 9 ( 2005-09-01), p. 2160-2167
    Kurzfassung: Because fruits and vegetables are rich in bioactive compounds with potential cancer-preventive actions, increased consumption may reduce the risk of ovarian cancer. Evidence on the association between fruit and vegetable intake and ovarian cancer risk has not been consistent. We analyzed and pooled the primary data from 12 prospective studies in North America and Europe. Fruit and vegetable intake was measured at baseline in each study using a validated food-frequency questionnaire. To summarize the association between fruit and vegetable intake and ovarian cancer, study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Among 560,441 women, 2,130 cases of invasive epithelial ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. Total fruit intake was not associated with ovarian cancer risk—the pooled multivariate RR for the highest versus the lowest quartile of intake was 1.06 [95% confidence interval (95% CI), 0.92-1.21; P value, test for trend = 0.73; P value, test for between-studies heterogeneity = 0.74]. Similarly, results for total vegetable intake indicated no significant association (pooled multivariate RR, 0.90; 95% CI, 0.78-1.04, for the highest versus the lowest quartile; P value, test for trend = 0.06; P value, test for between-studies heterogeneity = 0.31). Intakes of botanically defined fruit and vegetable groups and individual fruits and vegetables were also not associated with ovarian cancer risk. Associations for total fruits and vegetables were similar for different histologic types. These results suggest that fruit and vegetable consumption in adulthood has no important association with the risk of ovarian cancer.
    Materialart: Online-Ressource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-05-0218
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2005
    ZDB Id: 2036781-8
    ZDB Id: 1153420-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 22 ( 2021-11-15), p. 6095-6105
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 22 ( 2021-11-15), p. 6095-6105
    Kurzfassung: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling. Patients and Methods: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control. Results: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials. Conclusions: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans. See related commentary by Shastri and Adrianzen-Herrera, p. 6069
    Materialart: Online-Ressource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-21-0935
    RVK:
    XA 36791
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 1225457-5
    ZDB Id: 2036787-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    Online-Ressource
    Online-Ressource
    Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 2 ( 2011-02-01), p. 360-371
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 2 ( 2011-02-01), p. 360-371
    Kurzfassung: AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials. Mol Cancer Ther; 10(2); 360–71. ©2010 AACR.
    Materialart: Online-Ressource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-10-0760
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 2062135-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    Online-Ressource
    Online-Ressource
    Abstract A119: A proteomics-based approach to identify biomarker profiles of homologous recombination deficiency (HRD) in breast cancer cell lines
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. A119-A119
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A119-A119
    Kurzfassung: Background: The oral PARP inhibitor olaparib (AZD2281, KU-0059436) has been shown to have single agent clinical activity in tumors from patients with hereditary BRCA mutations (Fong et al., 2009). Pre-clinical studies have also shown sensitivity to PARP inhibition in cells deficient in non-BRCA components of the homologous recombination (HR) DNA repair and signalling pathways. These include proteins such as NBS1, ATM and CHK2 (McCabe et al., 2006), suggesting the broader clinical potential of PARP inhibitors in tumors that are HR deficient (HRD). Thus the ability to identify tumors with HRD will be critical to realising the full potential of this targeted therapy. A proteomics study analysing isogenic breast cancer cell lines in which key HR gene expression had been stably knocked down was performed to identify a broad protein biomarker profile which may contribute to this patient selection strategy. This study also offered the opportunity to identify novel HR associated proteins and a greater understanding of DNA damage responses. Methods: Nuclear or phospho-protein enriched samples from stable RNAi knockdown breast cancer cell lines (CAL51 and/or MCF7) for 6 key HR genes (BRCA1, BRCA2, ATM, CHEK2, MRE11, NBS1) were analysed using 2 dimensional-difference gel electrophoresis (2D-DIGE) in comparison with parental wild type and/or non specific control cells. The identities of proteins of interest were determined by mass spectrometry. Further analysis of these results was undertaken through bioinformatics approaches utilising the Ingenuity Pathway Analysis (IPA) and GeneGo software tools. Results: Significant differences in protein abundance were observed in 308 proteins through these proteomic analyses. In depth bioinformatics analysis of these results determined their functional roles, their relationship to the double strand break repair (DSBR) pathways such as HR and non homologous end joining (NHEJ) and DNA damage response (DDR) signalling through network modelling. Where no direct relationship was apparent for these putative HRD associated proteins, their linkage was explored back to the specific HR gene knocked down in the cell line that gave the protein abundance change result. The most consistent cellular functions and pathways associated with the protein changes across the different gene knock downs included cell death, post-translational modification and protein folding. Conclusions: The abrogation of key genes in the HR pathway leads to wide ranging effects on downstream cellular functions including cell death, post-translational modification and protein folding. These candidate biomarkers of HRD are being developed into a biomarker profile to predict response to olaparib in the clinic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A119.
    Materialart: Online-Ressource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-A119
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2009
    ZDB Id: 2062135-8
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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