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  1. Article: High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome.

    Jamshidi, Maral / Fagerholm, Rainer / Muranen, Taru A / Kaur, Sippy / Potdar, Swapnil / Khan, Sofia / Netti, Eliisa / Mpindi, John-Patrick / Yadav, Bhagwan / Kiiski, Johanna I / Aittomäki, Kristiina / Heikkilä, Päivi / Saarela, Jani / Bützow, Ralf / Blomqvist, Carl / Nevanlinna, Heli

    Cancers

    2021  Volume 13, Issue 12

    Abstract: Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from ... ...

    Abstract Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (
    Language English
    Publishing date 2021-06-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13122907
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.

    Kiiski, Johanna I / Fagerholm, Rainer / Tervasmäki, Anna / Pelttari, Liisa M / Khan, Sofia / Jamshidi, Maral / Mantere, Tuomo / Pylkäs, Katri / Bartek, Jiri / Bartkova, Jirina / Mannermaa, Arto / Tengström, Maria / Kosma, Veli-Matti / Winqvist, Robert / Kallioniemi, Anne / Aittomäki, Kristiina / Blomqvist, Carl / Nevanlinna, Heli

    International journal of cancer

    2016  Volume 139, Issue 12, Page(s) 2760–2770

    Abstract: Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, ... ...

    Abstract Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09-2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5-5.76, p = 1.80 × 10
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/therapy ; Combined Modality Therapy ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Female ; Genotype ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Neoplasm Grading ; Neoplasm Metastasis ; Neoplasm Staging ; Phenotype ; Point Mutation ; Population Surveillance ; Prognosis ; Proportional Hazards Models ; Treatment Outcome ; Young Adult
    Chemical Substances Biomarkers, Tumor ; FANCM protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
    Language English
    Publishing date 2016-12-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.30394
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 478: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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    Zs.MO 576: Show issues

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  3. Article ; Online: NQO1 expression correlates inversely with NFκB activation in human breast cancer.

    Jamshidi, Maral / Bartkova, Jirina / Greco, Dario / Tommiska, Johanna / Fagerholm, Rainer / Aittomäki, Kristiina / Mattson, Johanna / Villman, Kenneth / Vrtel, Radek / Lukas, Jiri / Heikkilä, Päivi / Blomqvist, Carl / Bartek, Jiri / Nevanlinna, Heli

    Breast cancer research and treatment

    2012  Volume 132, Issue 3, Page(s) 955–968

    Abstract: NQO1 participates in cellular defense against oxidative stress and regulates apoptosis via p53- and NFκB-mediated pathways. We have previously found that homozygous missense variant NQO1*2 (rs1800566) predicts poor survival among breast cancer patients, ... ...

    Abstract NQO1 participates in cellular defense against oxidative stress and regulates apoptosis via p53- and NFκB-mediated pathways. We have previously found that homozygous missense variant NQO1*2 (rs1800566) predicts poor survival among breast cancer patients, particularly after anthracycline-based adjuvant chemotherapy. Here, we investigated NQO1 and NFκB protein expression and global gene expression profiles in breast tumors with correlation to tumor characteristics and survival after adjuvant chemotherapy. We used immunohistochemical analysis of tissue microarrays to study NQO1 and NFκB expression in two series of tumors: 1000 breast tumors unselected for treatment and 113 from a clinical trial comparing chemotherapy regimens after anthracycline treatment in advanced breast cancer. We used gene expression arrays to define genes co-expressed with NQO1 and NFκB. NQO1 and nuclear NFκB were expressed in 83% and 11% of breast tumors, and correlated inversely (P = 0.012). NQO1 protein expression was associated with estrogen receptor (ER) expression (P = 0.011), whereas 34.5% of NFκB-nuclear/activated tumors were ER negative (P = 0.001). NQO1 protein expression and NFκB activation showed only trends, but no statistical significance for patient survival or outcome after anthracycline treatment. Gene expression analysis highlighted 193 genes that significantly correlated with both NQO1 and NFκB in opposite directions, consistent with the expression patterns of the two proteins. Inverse correlation was found with genes related to oxidation/reduction, lipid biosynthesis and steroid metabolism, immune response, lymphocyte activation, Jak-STAT signaling and apoptosis. The inverse relationship between NQO1 protein expression and NFκB activation, underlined also by inverse patterns of association with ER and gene expression profiles of tumors, suggests that NQO1-NFκB interaction in breast cancer is different from several other tissue types, possibly due to estrogen receptor signaling in breast cancer. Neither NQO1 nor NFκB protein expression appear as significant prognostic or predictive markers in breast cancer.
    MeSH term(s) Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/mortality ; Carcinoma, Ductal, Breast/genetics ; Carcinoma, Ductal, Breast/metabolism ; Carcinoma, Ductal, Breast/mortality ; Carcinoma, Lobular/genetics ; Carcinoma, Lobular/metabolism ; Carcinoma, Lobular/mortality ; Cell Nucleus/metabolism ; Female ; Gene Expression Profiling ; Humans ; NAD(P)H Dehydrogenase (Quinone)/genetics ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-kappa B/metabolism ; Oligonucleotide Array Sequence Analysis ; Proportional Hazards Models ; Regression Analysis
    Chemical Substances NF-kappa B ; NAD(P)H Dehydrogenase (Quinone) (EC 1.6.5.2) ; NQO1 protein, human (EC 1.6.5.2)
    Language English
    Publishing date 2012-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604563-7
    ISSN 1573-7217 ; 0167-6806
    ISSN (online) 1573-7217
    ISSN 0167-6806
    DOI 10.1007/s10549-011-1629-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1655: Show issues Location:
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  4. Article ; Online: MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer.

    Peurala, Hanna / Greco, Dario / Heikkinen, Tuomas / Kaur, Sippy / Bartkova, Jirina / Jamshidi, Maral / Aittomäki, Kristiina / Heikkilä, Päivi / Bartek, Jiri / Blomqvist, Carl / Bützow, Ralf / Nevanlinna, Heli

    PloS one

    2011  Volume 6, Issue 11, Page(s) e26122

    Abstract: MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links ... ...

    Abstract MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41-0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
    MeSH term(s) Biomarkers, Tumor/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Carcinoma, Ductal, Breast/genetics ; Carcinoma, Ductal, Breast/mortality ; Carcinoma, Ductal, Breast/secondary ; Carcinoma, Lobular/genetics ; Carcinoma, Lobular/mortality ; Carcinoma, Lobular/secondary ; Cyclin E/genetics ; DNA-Binding Proteins/genetics ; Female ; Gene Expression Profiling ; Histones/genetics ; Humans ; MicroRNAs/genetics ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Oligonucleotide Array Sequence Analysis ; Prognosis ; RNA, Messenger/genetics ; Receptor, ErbB-2/genetics ; Survival Rate ; Tissue Array Analysis ; Transcription Factors/genetics ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Biomarkers, Tumor ; Cyclin E ; DNA-Binding Proteins ; H2AX protein, human ; Histones ; MIRN34 microRNA, human ; MicroRNAs ; RNA, Messenger ; TP53 protein, human ; Transcription Factors ; Tumor Suppressor Protein p53 ; c-MYC-associated zinc finger protein ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2011-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0026122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome.

    Jamshidi, Maral / Schmidt, Marjanka K / Dörk, Thilo / Garcia-Closas, Montserrat / Heikkinen, Tuomas / Cornelissen, Sten / van den Broek, Alexandra J / Schürmann, Peter / Meyer, Andreas / Park-Simon, Tjoung-Won / Figueroa, Jonine / Sherman, Mark / Lissowska, Jolanta / Keong, Garrett Teoh Hor / Irwanto, Astrid / Laakso, Marko / Hautaniemi, Sampsa / Aittomäki, Kristiina / Blomqvist, Carl /
    Liu, Jianjun / Nevanlinna, Heli

    International journal of cancer

    2012  Volume 132, Issue 9, Page(s) 2044–2055

    Abstract: Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in ... ...

    Abstract Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.
    MeSH term(s) AMP-Activated Protein Kinases/genetics ; Adult ; Antineoplastic Agents, Hormonal/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Carcinoma, Ductal, Breast/drug therapy ; Carcinoma, Ductal, Breast/genetics ; Carcinoma, Ductal, Breast/mortality ; Carcinoma, Lobular/drug therapy ; Carcinoma, Lobular/genetics ; Carcinoma, Lobular/mortality ; Female ; Gene Regulatory Networks/genetics ; Genotype ; Germ-Line Mutation/genetics ; Humans ; Middle Aged ; Neoplasm Grading ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Nerve Tissue Proteins/genetics ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Phosphatase 2/genetics ; Proto-Oncogene Proteins c-mdm2/genetics ; RNA, Messenger/genetics ; RNA, Neoplasm/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Rate ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Antineoplastic Agents, Hormonal ; Nerve Tissue Proteins ; RNA, Messenger ; RNA, Neoplasm ; TP53 protein, human ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; PRKAG2 protein, human (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; PPP2R2B protein, human (EC 3.1.3.16) ; Protein Phosphatase 2 (EC 3.1.3.16)
    Language English
    Publishing date 2012-10-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.27884
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 478: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 576: Show issues

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  6. Article ; Online: TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

    Fagerholm, Rainer / Khan, Sofia / Schmidt, Marjanka K / García-Closas, Montserrat / Heikkilä, Päivi / Saarela, Jani / Beesley, Jonathan / Jamshidi, Maral / Aittomäki, Kristiina / Liu, Jianjun / Ali, H Raza / Andrulis, Irene L / Beckmann, Matthias W / Behrens, Sabine / Blows, Fiona M / Brenner, Hermann / Chang-Claude, Jenny / Couch, Fergus J / Czene, Kamila /
    Fasching, Peter A / Figueroa, Jonine / Floris, Giuseppe / Glendon, Gord / Guo, Qi / Hall, Per / Hallberg, Emily / Hamann, Ute / Holleczek, Bernd / Hooning, Maartje J / Hopper, John L / Jager, Agnes / Kabisch, Maria / Keeman, Renske / Kosma, Veli-Matti / Lambrechts, Diether / Lindblom, Annika / Mannermaa, Arto / Margolin, Sara / Provenzano, Elena / Shah, Mitul / Southey, Melissa C / Dennis, Joe / Lush, Michael / Michailidou, Kyriaki / Wang, Qin / Bolla, Manjeet K / Dunning, Alison M / Easton, Douglas F / Pharoah, Paul D P / Chenevix-Trench, Georgia / Blomqvist, Carl / Nevanlinna, Heli

    Oncotarget

    2017  Volume 8, Issue 11, Page(s) 18381–18398

    Abstract: TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53- ... ...

    Abstract TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Anthracyclines/therapeutic use ; Apoptosis Regulatory Proteins/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Female ; Genotype ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; SKP Cullin F-Box Protein Ligases/genetics ; Survival Analysis ; Treatment Outcome ; Tumor Suppressor Protein p53/genetics ; Young Adult
    Chemical Substances Anthracyclines ; Apoptosis Regulatory Proteins ; TP53 protein, human ; TP53BP2 protein, human ; Tumor Suppressor Protein p53 ; FBXO28 protein, human (EC 2.3.2.27) ; SKP Cullin F-Box Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2017-02-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.15110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival.

    Jamshidi, Maral / Fagerholm, Rainer / Khan, Sofia / Aittomäki, Kristiina / Czene, Kamila / Darabi, Hatef / Li, Jingmei / Andrulis, Irene L / Chang-Claude, Jenny / Devilee, Peter / Fasching, Peter A / Michailidou, Kyriaki / Bolla, Manjeet K / Dennis, Joe / Wang, Qin / Guo, Qi / Rhenius, Valerie / Cornelissen, Sten / Rudolph, Anja /
    Knight, Julia A / Loehberg, Christian R / Burwinkel, Barbara / Marme, Frederik / Hopper, John L / Southey, Melissa C / Bojesen, Stig E / Flyger, Henrik / Brenner, Hermann / Holleczek, Bernd / Margolin, Sara / Mannermaa, Arto / Kosma, Veli-Matti / Van Dyck, Laurien / Nevelsteen, Ines / Couch, Fergus J / Olson, Janet E / Giles, Graham G / McLean, Catriona / Haiman, Christopher A / Henderson, Brian E / Winqvist, Robert / Pylkäs, Katri / Tollenaar, Rob A E M / García-Closas, Montserrat / Figueroa, Jonine / Hooning, Maartje J / Martens, John W M / Cox, Angela / Cross, Simon S / Simard, Jacques / Dunning, Alison M / Easton, Douglas F / Pharoah, Paul D P / Hall, Per / Blomqvist, Carl / Schmidt, Marjanka K / Nevanlinna, Heli

    Oncotarget

    2015  Volume 6, Issue 35, Page(s) 37979–37994

    Abstract: In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, ... ...

    Abstract In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.
    MeSH term(s) Biomarkers, Tumor/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Female ; Humans ; NF-kappa B/genetics ; Neoplasm Grading ; Neoplasm Invasiveness ; Neoplasm Staging ; Polymorphism, Single Nucleotide/physiology ; Prognosis ; Signal Transduction ; Survival Rate
    Chemical Substances Biomarkers, Tumor ; NF-kappa B
    Language English
    Publishing date 2015-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.4991
    Database MEDical Literature Analysis and Retrieval System OnLINE

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