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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >DNA polymerase θ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability
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DNA polymerase θ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability

机译：DNA聚合酶θ上调与乳腺癌患者的不良生存率，扰乱DNA复制并促进遗传不稳定有关

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摘要

"Replicative stress" is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.
机译：“复制性应激”是肿瘤从早期发展起的主要因素之一。因此，参与DNA合成的基因可能代表了尚未充分开发的潜在癌症预后标志物来源。为此，我们从两个未经治疗的原发性乳腺癌患者的独立队列中（法国，n = 206；英国，n = 117）生成了基因表达谱。我们在此报告，在13种人类核DNA聚合酶基因中，与正常的乳腺组织相比，DNA聚合酶θ（POLQ）是乳腺癌中唯一一个明显上调的基因。重要的是，POLQ的上调与不良的临床结果显着相关（POLQ表达高的患者死亡风险增加了4.3倍），并且这种相关性与Cyclin E表达或阳性淋巴结数目无关，目前被认为是标志物结果差。因此，POLQ表达为Cyclin E肿瘤表达高或阳性淋巴结数目高的患者的生存结果提供了另外的指示。此外，为了破译乳腺癌中POLQ上调的分子后果，我们产生了稳定表达POLQ的人MRC5-SV细胞系。强大的POLQ表达直接与缺陷的DNA复制叉进展和染色体损伤有关。因此，POLQ的过表达可能是乳腺癌有希望的遗传不稳定性和预后的标志物。

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    Fanny Lemee; rnValerie Bergoglio; rnAnne Fernandez-Vidal; rnAlice Machado-Silva; rnMarie-Jeanne Pillaire; Anne Bieth; rnCatherine Gentil; rnLee Baker; rnAnne-Laure Martin; rnClaire Leduc; rnElena Lam; rnEddy Magdeleine; Thomas Filleron; rnNaiema Oumouhou; rnBernd Kaina; rnMineaki Seki; rnFanny Grimal; rnMagali Lacroix-Triki; Alastair Thompson; rnHenri Roche; rnJean-Christophe Bourdon; rnRichard D. Wood; rnJean-Sebastien Hoffmann; Christophe Cazaux;

  • 作者单位

    Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France European Associated Laboratory, University of Dundee, Institut National de la Sante et de la Recherche Medicale U858, Dundee DD1 9SY, United Kingdom;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnService d' Epidemiologie, Institut National de la Sante et de la Recherche Medicale U558, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse, Universite Paul Sabatier, 31073 Toulouse, France;

    rnDepartment of Surgery and Molecular Oncology, Ninewells Hospital, Dundee DD1 9SY, United Kingdom;

    rnFederation des Centres de Lutte Contre le Cancer, 75654 Paris, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnDepartment of Toxicology, University of Mainz, D-55131 Mainz, Germany;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnInstitut Claudius Regaud, Universite de Toulouse, Universite Paul Sabatier, 31052 Toulouse, France;

    rnService d' Epidemiologie, Institut National de la Sante et de la Recherche Medicale U558, Centre Hospitalier Universitaire de Toulouse, Universite de Toulouse, Universite Paul Sabatier, 31073 Toulouse, France;

    rnDepartment of Toxicology, University of Mainz, D-55131 Mainz, Germany;

    rnLaboratories for Organismal Biosystems, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan;

    rnDepartement d' Oncogenese et de Signalisation des Cellules Hematopoietiques, Institut National de la Sante et de la Recherche Medicale U563, Universite de Toulouse, Universite Paul Sabatier, 31059 Toulouse, France;

    rnInstitut Claudius Regaud, Universite de Toulouse, Universite Paul Sabatier, 31052 Toulouse, France;

    rnDepartment of Surgery and Molecular Oncology, Ninewells Hospital, Dundee DD1 9SY, United Kingdom;

    rnInstitut Claudius Regaud, Universite de Toulouse, Universite Paul Sabatier, 31052 Toulouse, France;

    rnEuropean Associated Laboratory, University of Dundee, Institut National de la Sante et de la Recherche Medicale U858, Dundee DD1 9SY, United Kingdom;

    rnScience Park-Research Division, University of Texas Graduate School of Biomedical Sciences at Houston, M. D. Anderson Cancer Center, Smithville, TX 78957;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

    rnCentre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale and Universite de Toulouse, Universite Paul Sabatier, 31077 Toulouse, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    specialized DNA replication; prognosis marker; S-phase checkpoint;

    机译：专门的DNA复制;预后标记S相检查点;

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