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Sample records for brca1 mrna expression

  1. Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

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    Rosell, Rafael; Perez-Roca, Laia; Sanchez, Jose Javier; Cobo, Manuel; Moran, Teresa; Chaib, Imane; Provencio, Mariano; Domine, Manuel; Sala, Maria Angeles; Jimenez, Ulpiano; Diz, Pilar; Barneto, Isidoro; Macias, Jose Antonio; de las Peñas, Ramon; Catot, Silvia; Isla, Dolores; Sanchez, Jose Miguel; Ibeas, Rafael; Lopez-Vivanco, Guillermo; Oramas, Juana; Mendez, Pedro; Reguart, Noemi; Blanco, Remei; Taron, Miquel

    2009-01-01

    Background Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. Methodology/Principal Findings We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1

  2. XPG mRNA expression levels modulate prognosis in resected non-small-cell lung cancer in conjunction with BRCA1 and ERCC1 expression.

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    Bartolucci, Roberta; Wei, Jia; Sanchez, Jose Javier; Perez-Roca, Laia; Chaib, Imane; Puma, Francesco; Farabi, Raffaele; Mendez, Pedro; Roila, Fausto; Okamoto, Tatsuro; Taron, Miquel; Rosell, Rafael

    2009-01-01

    Molecular markers can help identify patients with early-stage non-small-cell lung cancer (NSCLC) with a high risk of relapse. Excision repair cross-complementing 1 (ERCC1), Xeroderma pigmentosum group G (XPG), and breast cancer 1 (BRCA1) are involved in DNA damage repair, whereas ribonucleotide reductase M1 (RRM1) is implicated in DNA synthesis. Expression levels of these molecules might therefore have a prognostic role in lung cancer. We examined ERCC1, RRM1, XPG, and BRCA1 mRNA levels by real-time quantitative polymerase chain reaction in 54 patients with stage IB-IIB resected NSCLC. A strong correlation was observed between the 4 genes. For patients with low BRCA1, regardless of XPG mRNA expression levels, disease-free survival (DFS) was not reached. For patients with intermediate/high BRCA1 and high XPG, DFS was 50.7 months. However, for patients with intermediate/high BRCA1 and low/intermediate XPG, DFS decreased to 16.3 months (P = .002). Similar differences were observed in overall survival, with median survival not reached for patients with low BRCA1, regardless of XPG levels, or for patients with intermediate/high BRCA1 and high XPG. Conversely, for patients with intermediate/high BRCA1 levels and low/intermediate XPG levels, median survival dropped to 25.5 months (P = .007). BRCA1 and XPG were identified as independent prognostic factors for both median survival and DFS. High BRCA1 mRNA expression confers poor prognosis in early NSCLC, and the combination of high BRCA1 and low XPG expression still further increases the risk of shorter survival. These findings can help optimize the customization of adjuvant chemotherapy.

  3. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel

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    Wang Tingting

    2008-04-01

    Full Text Available Abstract Background One of the major challenges in currently chemotherapeutic theme is lacking effective biomarkers for drug response and sensitivity. Our current study focus on two promising biomarkers, ERCC1 (excision repair cross-complementing group 1 and BRCA1 (breast cancer susceptibility gene 1. To investigate their potential role in serving as biomarkers for drug sensitivity in cancer patients with metastases, we statistically measure the mRNA expression level of ERCC1 and BRCA1 in tumor cells isolated from malignant effusions and correlate them with cisplatin and/or docetaxel chemosensitivity. Methods Real-time quantitative PCR is used to analysis related genes expression in forty-six malignant effusions prospectively collected from non-small cell lung cancer (NSCLC, gastric and gynecology cancer patients. Viable tumor cells obtained from malignant effusions are tested for their sensitivity to cisplatin and docetaxel using ATP-TCA assay. Results ERCC1 expression level is negatively correlated with the sensitivity to cisplatin in NSCLC patients (P = 0.001. In NSCLC and gastric group, BRCA1 expression level is negatively correlated with the sensitivity to cisplatin (NSCLC: P = 0.014; gastric: P = 0.002 while positively correlated with sensitivity to docetaxel (NSCLC: P = 0.008; gastric: P = 0.032. A significant interaction is found between ERCC1 and BRCA1 mRNA expressions on sensitivity to cisplatin (P = 0.010, n = 45. Conclusion Our results demonstrate that ERCC1 and BRCA1 mRNA expression levels are correlated with in vitro chemosensitivity to cisplatin and/or docetaxel in malignant effusions of NSCLC and gastric cancer patients. And combination of ERCC1 and BRCA1 may have a better role on predicting the sensitivity to cisplatin than the single one is considered.

  4. BRCA1 mRNA expression as a predictive and prognostic marker in advanced esophageal squamous cell carcinoma treated with cisplatin- or docetaxel-based chemotherapy/chemoradiotherapy.

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    Yong Gao

    Full Text Available BACKGROUND: The molecular backgrounds that determine therapeutic effectiveness in esophageal cancer remain largely unknown. Breast cancer susceptibility gene 1 (BRCA1 expression has been found to switch the response to cisplatin- or paclitaxel-based chemotherapy. It remains unclear how variations in BRCA1 expression influence clinical outcomes in esophageal cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qPCR was performed to examine BRCA1 mRNA expressions in paraffin-embedded specimens from 144 patients with advanced or metastatic esophageal squamous cell carcinoma who received cisplatin- or docetaxel-based first-line treatments. RESULTS: Low BRCA1 mRNA expression correlated with increased response rate (RR; P = 0.025 and 0.017, respectively and median overall survival (mOS; P = 0.002 and P<0.001, respectively in cisplatin-based chemotherapy or chemoradiotherapy group and also correlated with decreased RR (P = 0.017 and 0.024, respectively and mOS (both P<0.001 in docetaxel-based chemotherapy or chemoradiotherapy group. Multivariate analysis revealed that low BRCA1 expression was an independent prognostic factor in cisplatin-based chemotherapy (HR 0.29; 95%CI 0.12-0.71; P = 0.007 or chemoradiotherapy (HR 0.12; 95%CI 0.04-0.37; P<0.001 group and higher risk for mortality in docetaxel-based chemotherapy (HR 5.02; 95%CI 2.05-12.28; P<0.001 or chemoradiotherapy (HR 7.02; 95%CI 2.37-27.77; P<0.001 group. CONCLUSIONS: BRCA1 mRNA expression could be used as a predictive and prognostic marker in esophageal cancer who underwent first-line cisplatin- or docetaxel-based treatments.

  5. Frequently increased epidermal growth factor receptor (EGFR copy numbers and decreased BRCA1 mRNA expression in Japanese triple-negative breast cancers

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    Sugiura Hiroshi

    2008-10-01

    Full Text Available Abstract Background Triple-negative breast cancer (estrogen receptor-, progesterone receptor-, and HER2-negative (TNBC is a high risk breast cancer that lacks specific therapy targeting these proteins. Methods We studied 969 consecutive Japanese patients diagnosed with invasive breast cancer from January 1981 to December 2003, and selected TNBCs based on the immunohistochemical data. Analyses of epidermal growth factor receptor (EGFR gene mutations and amplification, and BRCA1 mRNA expression were performed on these samples using TaqMan PCR assays. The prognostic significance of TNBCs was also explored. Median follow-up was 8.3 years. Results A total of 110 (11.3% patients had TNBCs in our series. Genotyping of the EGFR gene was performed to detect 14 known EGFR mutations, but none was identified. However, EGFR gene copy number was increased in 21% of TNBCs, while only 2% of ER- and PgR-positive, HER2-negative tumors showed slightly increased EGFR gene copy numbers. Thirty-one percent of TNBCs stained positive for EGFR protein by immunohistochemistry. BRCA1 mRNA expression was also decreased in TNBCs compared with controls. Triple negativity was significantly associated with grade 3 tumors, TP53 protein accumulation, and high Ki67 expression. TNBC patients had shorter disease-free survival than non-TNBC in node-negative breast cancers. Conclusion TNBCs have an aggressive clinical course, and EGFR and BRCA1 might be candidate therapeutic targets in this disease.

  6. Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients.

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    Ioannis Boukovinas

    Full Text Available BACKGROUND: Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC patients. METHODOLOGY AND PRINCIPAL FINDINGS: Tumor samples were collected from 102 chemotherapy-naïve advanced NSCLC patients treated with gemcitabine plus docetaxel as part of a randomized trial. RRM1, RRM2 and BRCA1 mRNA levels were assessed by quantitative PCR and correlated with response, time to progression and survival. As BRCA1 levels increased, the probability of response increased (Odds Ratio [OR], 1.09: p = 0.01 and the risk of progression decreased (hazard ratio [HR], 0.99; p = 0.36. As RRM1 and RRM2 levels increased, the probability of response decreased (RRM1: OR, 0.97; p = 0.82; RRM2: OR, 0.94; p<0.0001 and the risk of progression increased (RRM1: HR, 1.02; p = 0.001; RRM2: HR, 1.005; p = 0.01. An interaction observed between BRCA1 and RRM1 allowed patients to be classified in three risk groups according to combinations of gene expression levels, with times to progression of 10.13, 4.17 and 2.30 months (p = 0.001. Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy. CONCLUSIONS: The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies.

  7. Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer

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    Papadaki, C; Tsaroucha, E; Kaklamanis, L; Lagoudaki, E; Trypaki, M; Tryfonidis, K; Mavroudis, D; Stathopoulos, E; Georgoulias, V; Souglakos, J

    2011-01-01

    Background: We explored the predictive significance of BRCA1, TXR1 and TSP1 expression in non-small-cell lung cancer (NSCLC) patients treated with docetaxel in association with cisplatin or gemcitabine. Methods: To analyse BRCA1, TXR1 and TSP1 mRNA expression from microdissected primary tumours of 131 patients with stage IIIB (wet) and IV NSCLC, RT–qPCR was used. Results: The mRNA levels of TXR1/TSP1 were inversely correlated (Spearman's test: −0.37; P=0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; P=0.018), longer median progression-free survival (PFS; P=0.029) and median overall survival (mOS P=0.003), whereas high TSP1 expression was correlated with higher RR (P=0.035), longer PFS (P<0.001) and mOS (P<0.001). Higher BRCA1 mRNA expression was associated with higher RR (P=0.028) and increased PFS (P=0.021), but not mOS (P=0.4). Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent factor for increased PFS (HR 0.49; 95% CI 0.32–0.76; P<0.001) and mOS (HR 0.37; 95% CI 0.2–0.58; P<0.001), whereas high BRCA1 expression was correlated with increased PFS (HR 0.53; 95% CI 0.37–0.78; P=0.001). Conclusions: These data indicate that TXR1/TSP1 and BRCA1 expression could be used for the prediction of taxanes' resistance in the treatment of NSCLC. PMID:21157449

  8. The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

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    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose Javier; Gimenez-Capitan, Ana; Rodriguez, Ignacio; Vergenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2013-01-01

    Platinum-based chemotherapy is the standard first-line treatment for non-oncogene-addicted non-small cell lung cancers (NSCLCs) and the analysis of multiple DNA repair genes could improve current models for predicting chemosensitivity. We investigated the potential predictive role of components of the 53BP1 pathway in conjunction with BRCA1. The mRNA expression of BRCA1, MDC1, CASPASE3, UBC13, RNF8, 53BP1, PIAS4, UBC9 and MMSET was analyzed by real-time PCR in 115 advanced NSCLC patients treated with first-line platinum-based chemotherapy. Patients expressing low levels of both BRCA1 and 53BP1 obtained a median progression-free survival of 10.3 months and overall survival of 19.3 months, while among those with low BRCA1 and high 53BP1 progression-free survival was 5.9 months (P <0.0001) and overall survival was 8.2 months (P=0.001). The expression of 53BP1 refines BRCA1-based predictive modeling to identify patients most likely to benefit from platinum-based chemotherapy. PMID:24197907

  9. [Chinese multicenter randomized trial of customized chemotherapy based on BRCA1 (breast cancer susceptibility gene 1)-RAP80 (receptor-associated protein 80) mRNA expression in advanced non-small cell lung cancer (NSCLC) patients].

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    Wei, J; Qian, X P; Zou, Z Y; Wang, L F; Yu, L X; You, C W; Song, Y; Lu, H Y; Hu, W J; Yan, J; Xu, X X; Chen, X F; Li, X Y; Wu, Q F; Zhou, Y; Zhang, F L; Liu, B R

    2016-11-23

    Objective: BRCA1 (breast cancer susceptibility gene 1) and RAP80 (receptor-associated protein 80) play key roles in predicting chemosensitivity of platinum and taxanes. A randomized trial was carried out to compare non-selected cisplatin-based chemotherapy with therapy customized according to BRCA1 and RAP80 expression. Methods: Advanced stage NSCLC patients whose tumor specimen was sufficient for molecular analysis were randomized (1∶3) to the control or experimental arm. Patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin (Arm 1), those with intermediate/high RAP80 expression and low/intermediate BRCA1expression received docetaxel/cisplatin (Arm 2), and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone (Arm 3). The primary end point was progression-free survival (PFS). Results: 226 patients were screened and 124 were randomized in this trial. ORR in the four subgroups was 22.6%, 48.4%, 30.3% and 19.2%, respectively (P=0.08); PFS was 4.74, 5.59, 3.78 and 2.73 months, respectively (P=0.55); and OS was 10.82, 14.44, 10.86 and 10.86 months, respectively (P=0.84). The common adverse effects included neutropenia, nausea, anemia and fatigue. Conclusions: No statistically significant difference of ORR, PFS or OS is observed in the experimental arms compared with the control arm. Patients with low RAP80 mRNA levels have a trend of better survival and higher response rate to gemcitabine/cisplatin chemotherapy.

  10. High SINE RNA Expression Correlates with Post-Transcriptional Downregulation of BRCA1

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    Giovanni Bosco

    2013-04-01

    Full Text Available Short Interspersed Nuclear Elements (SINEs are non-autonomous retrotransposons that comprise a large fraction of the human genome. SINEs are demethylated in human disease, but whether SINEs become transcriptionally induced and how the resulting transcripts may affect the expression of protein coding genes is unknown. Here, we show that downregulation of the mRNA of the tumor suppressor gene BRCA1 is associated with increased transcription of SINEs and production of sense and antisense SINE small RNAs. We find that BRCA1 mRNA is post-transcriptionally down-regulated in a Dicer and Drosha dependent manner and that expression of a SINE inverted repeat with sequence identity to a BRCA1 intron is sufficient for downregulation of BRCA1 mRNA. These observations suggest that transcriptional activation of SINEs could contribute to a novel mechanism of RNA mediated post-transcriptional silencing of human genes.

  11. Distinct claudin expression characterizes BRCA1-related breast cancer

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    van Voss, Marise R. Heerma; van Diest, Paul J.; Smolders, Yvonne H. C. M.; Bart, Joost; van der Wall, Elsken; van der Groep, Petra

    2014-01-01

    AimsMembers of the claudin family are involved in cancer progression and are differentially expressed in subtypes of breast cancer. Breast cancers in BRCA1 germ line mutation carriers have distinct clinicopathological characteristics. Biomarkers that discriminate between BRCA1-related and sporadic

  12. Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer.

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    Bonanno, Laura; Costa, Carlota; Majem, Margarita; Sanchez, Jose-Javier; Rodriguez, Ignacio; Gimenez-Capitan, Ana; Molina-Vila, Miquel Angel; Vergnenegre, Alain; Massuti, Bartomeu; Favaretto, Adolfo; Rugge, Massimo; Pallares, Cinta; Taron, Miquel; Rosell, Rafael

    2016-05-14

    BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model. We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point. The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004). These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.

  13. Transgenic expression of BRCA1 disturbs hematopoietic stem and progenitor cells quiescence and function

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    Bai, Lin; Shi, Guiying; Zhang, Xu; Dong, Wei; Zhang, Lianfeng, E-mail: zhanglf@cnilas.org

    2013-10-15

    The balance between quiescence and proliferation of HSCs is an important regulator of hematopoiesis. Loss of quiescence frequently results in HSCs exhaustion, which underscores the importance of tight regulation of proliferation in these cells. Studies have indicated that cyclin-dependent kinases are involved in the regulation of quiescence in HSCs. BRCA1 plays an important role in the repair of DNA double-stranded breaks, cell cycle, apoptosis and transcription. BRCA1 is expressed in the bone marrow. However, the function of BRCA1 in HSCs is unknown. In our study, we generated BRCA1 transgenic mice to investigate the effects of BRCA1 on the mechanisms of quiescence and differentiation in HSCs. The results demonstrate that over-expression of BRCA1 in the bone marrow impairs the development of B lymphocytes. Furthermore, BRCA1 induced an increase in the number of LSKs, LT-HSCs, ST-HSCs and MPPs. A competitive transplantation assay found that BRCA1 transgenic mice failed to reconstitute hematopoiesis. Moreover, BRCA1 regulates the expression of p21{sup waf1}/cip1 and p57{sup kip2}, which results in a loss of quiescence in LSKs. Together, over-expression of BRCA1 in bone marrow disrupted the quiescent of LSKs, induced excessive accumulation of LSKs, and disrupted differentiation of the HSCs, which acts through the down-regulated of p21{sup waf1}/cip1 and p57{sup kip2}. - Highlights: • Over-expression of BRCA1 results in impaired B lymphocyte development. • BRCA1 transgenic mice disrupted the quiescent of LSKs, induced excessive accumulation of LSKs. • BRCA1 impairs the function of HSCs through the down-regulated of p21{sup waf1/cip1} and p57{sup kip2}.

  14. The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia.

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    Dkhissi, Fatima; Aggoune, Djamel; Pontis, Julien; Sorel, Nathalie; Piccirilli, Nathalie; LeCorf, Amélie; Guilhot, François; Chomel, Jean-Claude; Ait-Si-Ali, Slimane; Turhan, Ali G

    2015-09-01

    BCR-ABL induces an intrinsic genetic instability in chronic myeloid leukemia (CML). The protein breast cancer 1, early onset (BRCA1)-associated protein 1 (BAP1) is a deubiquitinase interacting with the DNA repair regulator BRCA1 and is frequently inactivated in many cancers. Here, we report that BAP1 mRNA and protein levels are downregulated in a BCR-ABL1-expressing hematopoietic cell line (UT-7/11). A decrease of BAP1 transcripts is also observed in newly diagnosed CML patients. Moreover, BAP1 protein levels are low or undetectable in CD34(+) cells from CML patients at diagnosis as compared with CD34(+) cells from normal donors. In addition, BRCA1 protein level is reduced in BCR-ABL1-expressing UT-7/11 cells. Finally, the enforced expression of BAP1 is associated with BRCA1 protein deubiquitination and restoration. These results demonstrate BAP1 as a major link with the BCR-ABL-induced downregulation of BRCA1 in CML. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  15. BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers.

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    Wang, Gui-Hua; Zhao, Chun-Mei; Huang, Ying; Wang, Wei; Zhang, Shu; Wang, Xudong

    2017-11-07

    The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in four digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry (IHC) on tissue microarrays. A total of 1546 samples of four types of cancer tissues, their matched adjacent non-tumor tissues, and corresponding benign tissues were studied respectively. IHC expression patterns of the two proteins and their correlation with patients' clinical parameters and overall survival were analyzed. The results showed that low expression of cytoplasmic BRCA1 and BRCA2 were commonly associated with advanced TNM stage, while high expression of nuclear BRCA1 was generally correlated with advanced tumor stages in these cancers. High expression of cytoplasmic BRCA1 and BRCA2 had significantly favorable overall survival in digestive system cancers; in contrast, BRCA1 nuclear expression usually predicted poor outcomes. We conclude that BRCA1 and BRCA2 could be used as clinicopathological biomarkers to evaluate the prognosis of digestive system cancers. Copyright © 2017. Published by Elsevier Inc.

  16. [Expression and clinical significance of BRCA1 in human esophageal squamous cell carcinoma].

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    Yang, Yi-xuan; Xue, Li-yan; Dong, Li-jia; Fu, Ming; Zhan, Qi-min; Tong, Tong

    2012-12-01

    To investigate the expression of BRCA1 in esophageal squamous cell carcinoma (ESCC) tissues and evaluate its correlation with clinicopathological features as well as the prognosis of ESCC patients. The expression of BRCA1 was detected by immunohistochemistry (IHC) in 201 specimens of T3 stage ESCC tissues and corresponding adjacent normal tissues using tissue microarray. The correlation between BRCA1 expression and clinicopathological features of ESCC was determined by chi-square analysis. The cumulative survival rate was analyzed by Kaplan-Meier method. The positive rate of BRCA1 expression in ESCC tissues was significantly higher than that in adjacent normal tissues [88.6% (178/201) vs. 36.8% (74/201), P 0.05). The results of Kaplan-Meier analysis indicated that ESCC patients with a higher positive rate of BRCA1 expression have a poorer prognosis (P < 0.05). The expression of BRCA1 is related to the occurrence and development of esophageal carcinoma. BRCA1 protein may serve as a new potential biomarker in estimating the biological behavior of ESCC.

  17. miR-342 regulates BRCA1 expression through modulation of ID4 in breast cancer.

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    Elisabetta Crippa

    Full Text Available A miRNAs profiling on a group of familial and sporadic breast cancers showed that miRNA-342 was significantly associated with estrogen receptor (ER levels. To investigate at functional level the role of miR-342 in the pathogenesis of breast cancer, we focused our attention on its "in silico" predicted putative target gene ID4, a transcription factor of the helix-loop-helix protein family whose expression is inversely correlated with that of ER. ID4 is expressed in breast cancer and can negatively regulate BRCA1 expression. Our results showed an inverse correlation between ID4 and miR-342 as well as between ID4 and BRCA1 expression. We functionally validated the interaction between ID4 and miR-342 in a reporter Luciferase system. Based on these findings, we hypothesized that regulation of ID4 mediated by miR-342 could be involved in the pathogenesis of breast cancer by downregulating BRCA1 expression. We functionally demonstrated the interactions between miR-342, ID4 and BRCA1 in a model provided by ER-negative MDA-MB-231 breast cancer cell line that presented high levels of ID4. Overexpression of miR-342 in these cells reduced ID4 and increased BRCA1 expression, supporting a possible role of this mechanism in breast cancer. In the ER-positive MCF7 and in the BRCA1-mutant HCC1937 cell lines miR-342 over-expression only reduced ID4. In the cohort of patients we studied, a correlation between miR-342 and BRCA1 expression was found in the ER-negative cases. As ER-negative cases were mainly BRCA1-mutant, we speculate that the mechanism we demonstrated could be involved in the decreased expression of BRCA1 frequently observed in non BRCA1-mutant breast cancers and could be implicated as a causal factor in part of the familial cases grouped in the heterogeneous class of non BRCA1 or BRCA2-mutant cases (BRCAx. To validate this hypothesis, the study should be extended to a larger cohort of ER-negative cases, including those belonging to the BRCAx class.

  18. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

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    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders

    2017-01-01

    BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance. Tumor...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient...

  19. BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

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    Harriet E Feilotter

    Full Text Available The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

  20. Simultaneous ATM/BRCA1/RAD51 expression variations associated with prognostic factors in Iranian sporadic breast cancer patients.

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    Hallajian, Zeinab; Mahjoubi, Frouzandeh; Nafissi, Nahid

    2017-07-01

    DNA double-strand breaks (DSBs) as a serious lesion are repaired by non-homologous end-joining and homologous recombination pathways. ATM, BRCA1, RAD51 genes are involved in HR pathways. While some studies have revealed individual expression changes of these genes in different types of cancer, there are limited studies attempting to evaluate correlation of expression variations of these genes in breast cancer pathogenesis. This study aimed to determine RAD51, ATM and BRCA1 gene expression level and its association with clinicopathological factors in fresh breast cancer tissues. Moreover, this study evaluates potential correlations among expression levels of these genes. 50 breast cancer tissues were collected and examined for BRCA1, RAD51 and ATM gene expression by Real Time PCR. Expression changes were analyzed with REST software version 2009. mRNA expression was reduced in all these three genes when compared with β-Actin as a control gene (P value ATM, BRCA1 and RAD51 gene down expression (P value ATM with stage (P value < 0.05), necrosis (P value < 0.05), perineural invasion (P value < 0.05), vascular invasion (P value < 0.01), malignancy (P value ≤ 0.001), PR (P value < 0.05) and ER status (P value < 0.01). In addition, there was a significant association between down expression of BRCA1 with Ki67 (P value ≤ 0.001). Moreover, there was a significant association between down expression of RAD51 with lymph node involvement (P value < 0.01), auxiliary lymph node metastasis (P value = 0.01), age (P = 0.001), grade (P value < 0.05) and PR status (P value < 0.05). This study suggests association between expression changes in several DSB repair genes in a common functional pathway in breast cancer and the significant association between abnormal expression of these genes and important clinical prognostic factors.

  1. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

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    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  2. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  3. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  4. BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.

    Directory of Open Access Journals (Sweden)

    Yoshiko Shimizu

    Full Text Available INTRODUCTION: Women with HER2(+ or triple negative/basal-like (TN/BL breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+ and/or TN/BL tumors. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU, followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+ or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA. CONCLUSION/SIGNIFICANCE: BRCA1-IRIS overexpression triggers aggressive

  5. Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors.

    Science.gov (United States)

    Joosse, Simon A; Brandwijk, Kim I M; Mulder, Lennart; Wesseling, Jelle; Hannemann, Juliane; Nederlof, Petra M

    2011-02-01

    About 10-20% of all breast carcinomas show a basal-like phenotype, while ∼ 90% of breast tumors from BRCA1-mutation carriers are of this subtype. There is growing evidence that BRCA1-mutated tumors are not just a specific subset of the basal-like tumors, but that (the majority of) basal-like tumors show a dysfunctional BRCA1 pathway. This has major treatment implications, because emerging regimens specifically targeting DNA repair mechanisms would then be most effective against these tumors. To further understand the involvement of BRCA1 deficiency in sporadic basal-like tumors, we investigated 41 basal-like tumors for BRCA1 mRNA expression by quantitative real-time polymerase chain reaction, BRCA1 promoter methylation, their genomic profile by array-CGH, and gene expression levels by whole genome expression arrays. Array-CGH results were compared to those of 34 proven BRCA1-mutated tumors. Basal-like tumors were subdivided into two equal groups: deficient and proficient in BRCA1 gene expression. The chromosomal makeup of BRCA1 deficient sporadic basal-like tumors was similar to that of BRCA1-mutated tumors. BRCA1 proficient sporadic basal-like tumors were more similar to nonbasal-like tumors. Only half of the basal-like breast tumors are actually deficient in BRCA1 expression. Gain of chromosome arm 3q is a marker for BRCA1 deficiency in hereditary and sporadic breast tumors. © 2010 Wiley-Liss, Inc.

  6. Expression of the BRCA1 gene in a breast tumor: Correlation with the effect of neoadjuvant chemotherapy

    Science.gov (United States)

    Tsyganov, M. M.; Ibragimova, M. K.; Deryusheva, I. V.; Slonimskaya, E. M.; Litviakov, N. V.

    2017-09-01

    Most current research is limited by only germinal mutations of the BRCA1 gene (more often 5382insC) and the number of studies, which characterize various somatic alterations of the BRCA1 gene in a tumor, namely the expression of this gene and its correlation with the efficiency of chemotherapy, which is scarce. Taking into account the data on the connection between the genetic mutation of BRCA1 with the high efficiency of the platinum medication one may suggest that the expression of the BRCA1 gene is also associated with the high sensitivity of the tumor to the platinum medication. Aim: to evaluate the correlation between the expression of the BRCA1 gene in a breast tumor with the neoadjuvant chemotherapy (NACT) efficiency. The research included 86 patients with BC. We evaluated the expression of BRCA1 in the tumor material before and after NACT. We established that objective response to NACT is connected with a high level of BRCA1 in the general group of patients (p = 0.01) and in case of docetaxel monotherapy (p < 0.05).

  7. Impacto prognóstico da expressão imuno-histoquímica do BRCA1 nos carcinomas mamários esporádicos Prognostic impact of BRCA1 immunohistochemistry expression in sporadic breast carcinomas

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    Alfredo Ribeiro-Silva

    2005-06-01

    Full Text Available INTRODUÇÃO: Embora mutações no BRCA1 sejam raras nos carcinomas mamários não-familiares, é comum haver perda de expressão da proteína codificada por esse gene. A importância prognóstica desse achado não está bem estabelecida. OBJETIVOS: analisar a expressão imuno-histoquímica do BRCA1 em carcinomas mamários esporádicos e comparar os resultados obtidos com dados clínicos e histopatológicos de importância prognóstica. MATERIAL E MÉTODO: 102 carcinomas ductais sem outras especificações foram submetidos ao método imuno-histoquímico com os anticorpos BRCA1, RE, RP, p53, c-erbB-2 e Ki67. Os dados clínicos foram obtidos dos prontuários médicos. RESULTADOS: No epitélio normal, o BRCA1 apresentou apenas marcação nuclear, enquanto os carcinomas apresentaram tanto marcação nuclear quanto a citoplasmática. Os carcinomas com baixa expressão imuno-histoquímica do BRCA1 foram pouco diferenciados, com alta taxa proliferativa, negativos para receptores hormonais e positivos para c-erbB-2. Não houve correlação da expressão do BRCA1 com idade, estado menstrual, tamanho tumoral, acometimento de linfonodos, estadiamento patológico e expressão do p53. As sobrevidas média e livre de doença das pacientes cujos tumores expressaram menos e mais de 25% de marcação para o BRCA1 nas células neoplásicas foram de 4,2 e 3,9; e 7,8 e 6,3 anos, respectivamente.BACKGROUND: Although mutations in BRCA are rare in non familiar breast carcinomas, it is common the lost of expression of the protein codified by this gene. The prognostic importance of this finding is not well established. OBJECTIVES: to analyze the immunohistochemistry expression of BRCA1 in sporadic breast carcinomas and to compare the results with clinical and histopathologic data of prognostic significance. MATERIAL AND METHOD: 102 NOS ductal carcinomas were submitted to the immunohistochemistry method with the antibodies BRCA1, ER, PR, p53, c-erbB-2 and Ki67. The

  8. Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mitra, A V; Jameson, C; Barbachano, Y

    2010-01-01

    Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic...... feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant...... a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all...

  9. Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

    NARCIS (Netherlands)

    Heerma van Voss, Marise R.; van der Groep, Petra; Bart, Joost; van der Wall, Elsken; van Diest, Paul J.

    Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells

  10. BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility - A proteomics study.

    Science.gov (United States)

    Gau, David M; Lesnock, Jamie L; Hood, Brian L; Bhargava, Rohit; Sun, Mai; Darcy, Kathleen; Luthra, Soumya; Chandran, Uma; Conrads, Thomas P; Edwards, Robert P; Kelley, Joseph L; Krivak, Thomas C; Roy, Partha

    2015-01-01

    Functional loss of expression of breast cancer susceptibility gene 1(BRCA1) has been implicated in genomic instability and cancer progression. There is emerging evidence that BRCA1 gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1(+/+) and BRCA1(null) status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells.

  11. BRCA1 Expression Is Epigenetically Repressed in Sporadic Ovarian Cancer Cells by Overexpression of C-Terminal Binding Protein 2

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    Taymaa May

    2013-06-01

    Full Text Available INTRODUCTION: Ovarian cancer is the leading cause of mortality from gynecological malignancy despite advancements in novel therapeutics. We have recently demonstrated that the transcriptional co-repressor C-terminal binding protein 2 (CtBP2 is overexpressed in epithelial ovarian carcinoma. MATERIALS AND METHODS: Reverse-transcribed cDNA from CtBP2 wild-type and knockdown ovarian cancer cell lines was hybridized to Affymetrix Gene 1.0 ST microarrays, and differentially expressed genes were studied. Immunohistochemical analysis of CtBP2 and BRCA1 staining of ovarian tissues was performed. Chromatin immunoprecipitation (ChIP and luciferase assays were carried out. The effect of the drugs 4-methylthio-2-oxobutyric acid (MTOB and poly(ADP-ribose polymerase (PARP inhibitor Olaparib on CtBP2 wild-type and knockdown cell lines was examined using methylthiazol tetrazolium assays and an xCELLigence System. RESULTS: Eighty-five genes involved in DNA repair, mitotic checkpoint, nucleosome assembly, and the BRCA1 network were differentially regulated by CtBP2 expression. ChIP and luciferase reporter assays using a BRCA1 promoter-regulated luciferase construct indicated that the CtBP2 complex binds the BRCA1 promoter and represses BRCA1 transcription. Immunohistochemistry illustrated a significant inverse CtBP2 and BRCA1 expression in a panel of malignant ovarian tumor tissues. The CtBP2 inhibitor MTOB suppressed ovarian cancer cell survival in a CtBP2-dependent manner. Ovarian cancer cells with CtBP2 knockdown did not display increased sensitivity to the PARP inhibitor Olaparib. CONCLUSION: CtBP2 is an ovarian cancer oncogene that may play a significant role in epigenetically silencing BRCA1 function in sporadic epithelial ovarian cancer. CtBP2-specific inhibitors, such as MTOB, may be effective adjunct therapies in the management of patients with CtBP2-positive ovarian carcinoma.

  12. Epigenetic modulation of BRCA1 and BRCA2 gene expression by equol in breast cancer cell lines.

    Science.gov (United States)

    Bosviel, Rémy; Durif, Julie; Déchelotte, Pierre; Bignon, Yves-Jean; Bernard-Gallon, Dominique

    2012-10-01

    S-Equol is a metabolite resulting from the conversion of daidzein, a soya phyto-oestrogen, by the gut microflora. The potential protective effects of equol in breast cancer are still under debate. Consequently, we investigated the effects of equol on DNA methylation of breast cancer susceptibility genes (BRCA1 and BRCA2) and oncosuppressors in breast cancer cell lines (MDA-MB-231 and MCF-7) and in a dystrophic breast cell line (MCF-10a) following exposure to S-equol (2 μm) for 3 weeks. We demonstrated by quantitative analysis of methylated alleles a significant decrease in the methylation of the cytosine phosphate guanine (CpG) islands in the promoters of BRCA1 and BRCA2 after the S-equol treatment in MCF-7 and MDA-MB-231 cells and a trend in MCF-10a cells. We also showed that S-equol increases BRCA1 and BRCA2 protein expression in the nuclei and the cytoplasm in MCF-7, MDA-MB-231 and MCF-10a cell lines by immunohistochemistry. The increase in BRCA1 and BRCA2 proteins was also found after Western blotting in the studied cell lines. In summary, we demonstrated the demethylating effect of S-equol on the CpG islands inside the promoters of BRCA1 and BRCA2 genes, resulting in an increase in the level of expressed oncosuppressors in breast cancer cell lines.

  13. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

    LENUS (Irish Health Repository)

    Stordal, Britta

    2013-06-01

    Mutations in BRCA1\\/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1\\/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1\\/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1\\/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1\\/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1\\/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1\\/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1\\/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1\\/2 deleterious mutations 1\\/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective

  14. Loss of BRCA1 protein expression as indicator of the BRCAness phenotype is associated with favorable overall survival after complete resection of sporadic ovarian cancer.

    Science.gov (United States)

    Radosa, Marc P; Häfner, Norman; Camara, Oumar; Diebolder, Herbert; Mothes, Anke; Winzer, Harald; Jansen, Lars; Dürst, Matthias; Runnebaum, Ingo B

    2011-11-01

    Hereditary epithelial ovarian cancers (EOCs) not expressing functional BRCA1 protein are characterized by defects in homologous recombination DNA repair, rendering such tumors more sensitive to DNA damaging agents and synthetic lethality, that is, poly-ADP-ribose-polymerase inhibitor treatment. The aim of this study was to evaluate the use of BRCA1 immunohistochemistry (IHC) for EOC prognosis and identification of features of the BRCAness phenotype. Twenty-seven patients who were treated for advanced EOC by macroscopic complete surgical tumor resection and first-line carboplatin/paclitaxel treatment were included. Time to recurrence and overall survival time after initial surgery were determined, and patients' samples were evaluated for BRCA1 expression by IHC. BRCA1 messenger RNA expression and promoter methylation was analyzed to elucidate regulatory mechanisms involved in BRCA1 protein loss. BRCA1 IHC-negative patients had a significantly longer overall survival (crude rate, 1537 days) compared to the BRCA1 IHC-positive group (crude rate, 827 days; P = 0.01). The patients in the BRCA1 IHC-negative group were significantly younger (51 years) compared to BRCA1 IHC-positive patients (61 years; P IHC negativity of sporadic EOC may be predictive of sensitivity to platinum-based chemotherapy and the poly-ADP-ribose-polymerase inhibitor-sensitive BRCAness phenotype.

  15. No association between BRCA1 immunohistochemical expression and tumor grade, stage or overall survival in platinum-treated epithelial ovarian cancer patients.

    Science.gov (United States)

    Shawky, Abd El-Aty; El-Hafez, Amal Abd; El-Tantawy, Dina; Hamdy, Rasha

    2014-01-01

    The aim of this work is to assess the frequency of BRCA1 protein immunohistochemical (IHC) expression in epithelial ovarian cancer (EOC) and to evaluate the association of BRCA1 expression with clinical and pathological characteristics and the overall survival (OS) of patients treated with postoperative platinum- based chemotherapeutic agents. This retrospective study was conducted on 35 cases of epithelial ovarian cancer selected from the files of the Pathology Department, Faculty of Medicine, Mansoura University, Egypt. Immunohistochemistry (IHC) was performed for BRCA1 gene protein. BRCA1 expression was compared to patient's age, tumor histology, grade, stage and OS time. Statistical analysis was carried out with the SPSS version 16.0 to assess significant associations. BRCA1 nuclear expression was detected in 40% of EOC, in which a mild increase in the percentage of positive cases was observed with serous histology, stage IV, and grade 3 carcinomas. There was a significant statistical difference in BRCA1 expression with regard to histological subtypes of EOC (p=0.048), but not grade or stage. Mean OS and survival rate were slightly better for BRCA1 expressing group, but there was no statistically significant difference (p=0.528). No association between BRCA1 immunohistochemical expression and tumor grade, stage or overall survival was noted in platinum-treated epithelial ovarian cancer patients.

  16. Use of DNA-damaging agents and RNA pooling to assess expression profiles associated with BRCA1 and BRCA2 mutation status in familial breast cancer patients.

    Directory of Open Access Journals (Sweden)

    Logan C Walker

    2010-02-01

    Full Text Available A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes, BRCA1 and BRCA2. Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA-damaging agents (irradiation and mitomycin C on cellular response in relation to BRCA1 and BRCA2 mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs derived from affected women in high-risk breast cancer families (nine BRCA1, nine BRCA2, and nine non-BRCA1/2 or BRCAX individuals and nine LCLs from healthy individuals. Using an RNA-pooling strategy, we found that treating LCLs with 1.2 microM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate BRCA1, BRCA2, and BRCAX mutation status. A classifier was built using the expression profile of nine QRT-PCR validated genes that were associated with BRCA1, BRCA2, and BRCAX status in RNA pools. These nine genes could distinguish BRCA1 from BRCA2 carriers with 83% accuracy in individual samples, but three-way analysis for BRCA1, BRCA2, and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to BRCA1 and BRCA2 mutation carriers, non-BRCA1/2 (BRCAX individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from BRCA1, BRCA2, and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis.

  17. miRNA expression patterns in normal breast tissue and invasive breast cancers of BRCA1 and BRCA2 germ-line mutation carriers

    NARCIS (Netherlands)

    Vos, Shoko; Vesuna, Farhad; Raman, Venu; van Diest, Paul J.; van der Groep, Petra

    2015-01-01

    miRNA deregulation has been found to promote carcinogenesis. Little is known about miRNA deregulation in hereditary breast tumors as no miRNA expression profiling studies have been performed in normal breast tissue of BRCA1 and BRCA2 mutation carriers. miRNA profiles of 17 BRCA1- and 9

  18. Gene Expression Profiling in Hereditary, BRCA1-linked Breast Cancer: Preliminary Report

    Directory of Open Access Journals (Sweden)

    Dudaladava Volha

    2006-01-01

    Full Text Available Abstract Global analysis of gene expression by DNA microarrays is nowadays a widely used tool, especially relevant for cancer research. It helps the understanding of complex biology of cancer tissue, allows identification of novel molecular markers, reveals previously unknown molecular subtypes of cancer that differ by clinical features like drug susceptibility or general prognosis. Our aim was to compare gene expression profiles in breast cancer that develop against a background of inherited predisposing mutations versus sporadic breast cancer. In this preliminary study we analysed seven hereditary, BRCA1 mutation-linked breast cancer tissues and seven sporadic cases that were carefully matched by histopathology and ER status. Additionally, we analysed 6 samples of normal breast tissue. We found that while the difference in gene expression profiles between tumour tissue and normal breast can be easily recognized by unsupervised algorithms, the difference between those two types of tumours is more discrete. However, by supervised methods of data analysis, we were able to select a set of genes that may differentiate between hereditary and sporadic tumours. The most significant difference concerns genes that code for proteins engaged in regulation of transcription, cellular metabolism, signalling, proliferation and cell death. Microarray results for chosen genes (TOB1, SEPHS2 were validated by real-time RT-PCR.

  19. Gene Expression Profiling in Hereditary, BRCA1-linked Breast Cancer: Preliminary Report

    Science.gov (United States)

    2006-01-01

    Global analysis of gene expression by DNA microarrays is nowadays a widely used tool, especially relevant for cancer research. It helps the understanding of complex biology of cancer tissue, allows identification of novel molecular markers, reveals previously unknown molecular subtypes of cancer that differ by clinical features like drug susceptibility or general prognosis. Our aim was to compare gene expression profiles in breast cancer that develop against a background of inherited predisposing mutations versus sporadic breast cancer. In this preliminary study we analysed seven hereditary, BRCA1 mutation-linked breast cancer tissues and seven sporadic cases that were carefully matched by histopathology and ER status. Additionally, we analysed 6 samples of normal breast tissue. We found that while the difference in gene expression profiles between tumour tissue and normal breast can be easily recognized by unsupervised algorithms, the difference between those two types of tumours is more discrete. However, by supervised methods of data analysis, we were able to select a set of genes that may differentiate between hereditary and sporadic tumours. The most significant difference concerns genes that code for proteins engaged in regulation of transcription, cellular metabolism, signalling, proliferation and cell death. Microarray results for chosen genes (TOB1, SEPHS2) were validated by real-time RT-PCR. PMID:20223001

  20. Expression of BRCA1, HER-1 (EGFR) and HER-2 in sporadic breast cancer and relationships to other clinicopathological prognostic features.

    Science.gov (United States)

    Ansquer, Yan; Mandelbrot, Laurent; Lehy, Thérèse; Salomon, Laurence; Dhainaut, Caroline; Madelenat, Patrick; Feldmann, Gérard; Walker, Francine

    2005-01-01

    The BRCA1 caretaker gene is associated with poor prognostic features in hereditary breast cancer and may also play a role in sporadic breast cancer (SBC). HER-1 and HER-2 overexpression is associated with adverse prognosis in SBC. We studied whether BRCA1 expression was associated with HER1, HER2 and other prognostic features in SBC. Fifty newly-diagnosed SBC patients were studied for prognostic features and immunohistochemical expressions of BRCA1, HER-1 and HER-2. Tumors were positive for BRCA1 in 26%, HER-1 in 32% and HER-2 in 20% of cases. Lack of BRCA1 expression was associated with node metastases and decreased estrogen receptor. HER-2 expression was associated with young age, HER-1, Ki67 and decreased hormone receptors. No correlation was observed between BRCA1 and HER-1 or HER-2. In SBC, the lack of BRCA1 expression was associated with poor prognostic features, but unrelated to HER-1 and HER-2. HER2 and HER-1 were, however, highly correlated.

  1. Use of Gene Expression Profiles of Peripheral Blood Lymphocytes to Distinguish BRCA1 Mutation Carriers in High Risk Breast Cancer Families

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    Marie-Laure Vuillaume

    2009-01-01

    Full Text Available Mutations in two major genes, BRCA1 and BRCA2, account for up to 30% of families with hereditary breast cancer. Unfortunately, in most families there is little to indicate which gene should be targeted first for mutation screening, which is labor intensive, time consuming and often prohibitively expensive. As BRCA1 is a tumor suppressor gene involved in various cellular processes, heterozygous mutations could deregulate dependent pathways, such as DNA damage response, and disturb transcriptional activity of genes involved in the downstream signaling cascade. We investigated gene expression profiling in peripheral blood lymphocytes to evaluate this strategy for distinguishing BRCA1 mutation carriers from non-carriers. RNA from whole blood samples of 15 BRCA1 mutation carriers and 15 non-carriers from BRCA1 or BRCA2 families were hybridized to Agilent Technologies Whole Human Genome OligoMicroarrays (4 × 44 K multiplex format containing 41,000 unique human genes and transcripts. Gene expression data were analyzed with Welch’s t-tests and submitted to hierarchical clustering (GeneSpring GX software, Agilent Technologies. Statistical analysis revealed a slight tendency for 133 genes to be differentially expressed between BRCA1 mutation carriers and non-carriers. However, hierarchical clustering of these genes did not accurately discriminate BRCA1 mutation carriers from non-carriers. Expression variation for these genes according to BRCA1 mutation status was weak. In summary, microarray profiling of untreated whole blood does not appear to be informative in identifying breast cancer risk due to BRCA1 mutation.

  2. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

    DEFF Research Database (Denmark)

    Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Tuckova, Lucie

    2016-01-01

    Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Hi...

  3. Ubc9 mediates nuclear localization and growth suppression of BRCA1 and BRCA1a proteins.

    Science.gov (United States)

    Qin, Yunlong; Xu, Jingyao; Aysola, Kartik; Begum, Nurjahan; Reddy, Vaishali; Chai, Yuli; Grizzle, William E; Partridge, Edward E; Reddy, E Shyam P; Rao, Veena N

    2011-12-01

    BRCA1 gene mutations are responsible for hereditary breast and ovarian cancers. In sporadic breast tumors, BRCA1 dysfunction or aberrant subcellular localization is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein and the reason for cytoplasmic localization of BRCA1 in young breast cancer patients is not yet known. We have previously reported BRCA1 proteins unlike K109R and cancer-predisposing mutant C61G to bind Ubc9 and modulate ER-α turnover. In the present study, we have examined the consequences of altered Ubc9 binding and knockdown on the subcellular localization and growth inhibitory function of BRCA1 proteins. Our results using live imaging of YFP, GFP, RFP-tagged BRCA1, BRCA1a and BRCA1b proteins show enhanced cytoplasmic localization of K109 R and C61G mutant BRCA1 proteins in normal and cancer cells. Furthermore, down-regulation of Ubc9 in MCF-7 cells using Ubc9 siRNA resulted in enhanced cytoplasmic localization of BRCA1 protein and exclusive cytoplasmic retention of BRCA1a and BRCA1b proteins. These mutant BRCA1 proteins were transforming and impaired in their capacity to inhibit growth of MCF-7 and CAL51 breast cancer cells. Interestingly, cytoplasmic BRCA1a mutants showed more clonogenicity in soft agar and higher levels of expression of Ubc9 than parental MCF7 cells. This is the first report demonstrating the physiological link between cytoplasmic mislocalization of mutant BRCA1 proteins, loss of ER-α repression, loss of ubiquitin ligase activity and loss of growth suppression of BRCA1 proteins. Thus, binding of BRCA1 proteins to nuclear chaperone Ubc9 provides a novel mechanism for nuclear import and control of tumor growth. Copyright © 2011 Wiley-Liss, Inc.

  4. BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression.

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    Nic Waddell

    2008-05-01

    Full Text Available The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases. 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS. BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%, poor for BRCAX with an LCS (40-50%, and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%. This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

  5. The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

    DEFF Research Database (Denmark)

    Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina

    2016-01-01

    and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR......Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression...... carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance...

  6. Expression and clinical implication of Beclin1, HMGB1, p62, survivin, BRCA1 and ERCC1 in epithelial ovarian tumor tissues.

    Science.gov (United States)

    Ju, L-L; Zhao, C Y; Ye, K-F; Yang, H; Zhang, J

    2016-05-01

    The aim of the present study is to investigate the differential expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 protein in epithelial ovarian cancer (EOC) and to evaluate the relationship between autophagy and platinum resistance of EOC patients during platinum-based chemotherapy with the protein expression. Expression of Beclin1, HMGB1, p62, survivin, ERCC1 and BRCA1 were detected with immunohistochemistry in 60 patients, including 39 with epithelial ovarian cancer (EOC), 13 benign epithelial ovarian tumor tissue (BET) and 8 borderline ovarian tumor tissue. Beclin, p62 and ERCC1 expression was significantly higher in the EOC than the BET (p0.05). BRCA1 expression was lower in EOC than BET (pepithelial ovarian cancer.

  7. Breast cancer 1 (BrCa1 may be behind decreased lipogenesis in adipose tissue from obese subjects.

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    Francisco J Ortega

    Full Text Available CONTEXT: Expression and activity of the main lipogenic enzymes is paradoxically decreased in obesity, but the mechanisms behind these findings are poorly known. Breast Cancer 1 (BrCa1 interacts with acetyl-CoA carboxylase (ACC reducing the rate of fatty acid biosynthesis. In this study, we aimed to evaluate BrCa1 in human adipose tissue according to obesity and insulin resistance, and in vitro cultured adipocytes. RESEARCH DESIGN AND METHODS: BrCa1 gene expression, total and phosphorylated (P- BrCa1, and ACC were analyzed in adipose tissue samples obtained from a total sample of 133 subjects. BrCa1 expression was also evaluated during in vitro differentiation of human adipocytes and 3T3-L1 cells. RESULTS: BrCa1 gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002 and subcutaneous (SC; 1.49-fold, p = 0.001 adipose tissue from obese subjects. In parallel with increased BrCa1 mRNA, P-ACC was also up-regulated in SC (p = 0.007 as well as in OM (p = 0.010 fat from obese subjects. Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p<0.0001 and protein (1.2-fold, p = 0.001 were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-ACC decreased during differentiation of human adipocytes (p = 0.005 allowing lipid biosynthesis. Interestingly, BrCa1 gene expression in mature adipocytes was restored by inflammatory stimuli (macrophage conditioned medium, whereas lipogenic genes significantly decreased. CONCLUSIONS: The specular findings of BrCa1 and lipogenic enzymes in adipose tissue and adipocytes reported here suggest that BrCa1 might help to control fatty acid biosynthesis in adipocytes and adipose tissue from obese subjects.

  8. DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers.

    Science.gov (United States)

    Vaclová, Tereza; Gómez-López, Gonzalo; Setién, Fernando; Bueno, José María García; Macías, José Antonio; Barroso, Alicia; Urioste, Miguel; Esteller, Manel; Benítez, Javier; Osorio, Ana

    2015-07-01

    BRCA1 germline mutations increase the lifetime risk of developing breast and ovarian cancers. However, taking into account the differences in disease manifestation among mutation carriers, it is probable that different BRCA1 mutations have distinct haploinsufficiency effects and lead to the formation of different phenotypes. Using lymphoblastoid cell lines derived from heterozygous BRCA1 mutation carriers and non-carriers, we investigated the haploinsufficiency effects of various mutation types using qPCR, immunofluorescence, and microarray technology. Lymphoblastoid cell lines carrying a truncating mutation showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or those harboring a missense mutation, indicating greater spontaneous DNA damage. Cells carrying either BRCA1 mutation type showed impaired RAD51 foci formation, suggesting defective repair in mutated cells. Moreover, compared to controls, cell lines carrying missense mutations displayed a more distinct expression profile than cells with truncating mutations, which is consistent with different mutations giving rise to distinct phenotypes. Alterations in the immune response pathway in cells harboring missense mutations point to possible mechanisms of breast cancer initiation in carriers of these mutations. Our findings offer insight into how various heterozygous mutations in BRCA1 could lead to impairment of BRCA1 function and provide strong evidence of haploinsufficiency in BRCA1 mutation carriers.

  9. Inhibition of E2-induced expression of BRCA1 by persistent organochlorines

    DEFF Research Database (Denmark)

    Rattenborg, Thomas; Gjermandsen, Irene; Bonefeld-Jørgensen, Eva Cecilie

    2002-01-01

    BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved in the init......BACKGROUND: Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved...... in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter...

  10. Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

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    Craig B Bennett

    Full Text Available BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1 to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34 and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1. Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII carboxy terminal domain (P-CTD, phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1

  11. Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy.

    Science.gov (United States)

    Albarakati, Nada; Abdel-Fatah, Tarek M A; Doherty, Rachel; Russell, Roslin; Agarwal, Devika; Moseley, Paul; Perry, Christina; Arora, Arvind; Alsubhi, Nouf; Seedhouse, Claire; Rakha, Emad A; Green, Andrew; Ball, Graham; Chan, Stephen; Caldas, Carlos; Ellis, Ian O; Madhusudan, Srinivasan

    2015-01-01

    BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n = 1602 sporadic and n = 50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  12. Increased ID4 expression, accompanied by mutant p53 accumulation and loss of BRCA1/2 proteins in triple-negative breast cancer, adversely affects survival.

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    Thike, Aye A; Tan, Puay H; Ikeda, Murasaki; Iqbal, Jabed

    2016-04-01

    Breast cancer 1 (BRCA1) expression is down-regulated in a significant proportion of non-hereditary breast cancers, in the absence of any mutation. This phenomenon is more pronounced in oestrogen (ER)-negative tumours. Recent studies have suggested that inhibitor of DNA binding 4 (ID4), as well as p53, participate in the transcriptional regulation of BRCA1. Immunohistochemical expression of ID4, BRCA1, BRCA2 and p53 in 699 women with triple-negative breast cancer was investigated using tissue microarrays. The prognostic role of these biomarkers was also evaluated. Survival outcomes were estimated with the Kaplan-Meier method and compared between groups with log-rank statistics. Loss of BRCA1 and BRCA2 expression and overexpression of ID4 and p53 was observed in 75%, 90%, 95% and 66% of tumours, respectively. ID4 expression was increased in higher tumour grade (P P P = 0.037) and p53 accumulation (P triple-negative breast cancers (P = 0.041) and basal-like triple-negative breast cancers (P = 0.026). There is frequent ID4 expression and concomitant loss of BRCA proteins in triple-negative breast cancer. We hypothesize that strong ID4 expression could be useful as a prognostic marker in triple-negative breast cancer, predicting early tumour recurrence. © 2015 John Wiley & Sons Ltd.

  13. Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients

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    See-Hyoung Park

    2015-08-01

    Full Text Available BACKGROUND: Poly(ADP-ribose polymerase 1 (PARP1, γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS, and relapse-free survival (RFS by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph was an additional independent prognostic predictor for OS (P < .001 and RFS (P < .001. The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1 subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4 subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

  14. Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients.

    Science.gov (United States)

    Pirouzpanah, Saeed; Taleban, Forough-Azam; Mehdipour, Parvin; Atri, Morteza

    2015-08-01

    Dietary methyl group donors could influence the hypermethylation status of certain putative genes. The present study explored the possible associations of dietary intake of one-carbon metabolism-related nutrients with promoter hypermethylation status and expression of retinoic acid receptor-beta (RARB), breast cancer-1 (BRCA1), and Ras association domain family-1, isoform A (RASSF1A) genes in Iranian women with breast cancer (BC). The hypermethylation status was investigated in 146 dissected BC tissue samples using methylation-specific PCR. The expression level was evaluated by real-time RT-PCR. Dietary nutrients were estimated using a validated 136-item food frequency questionnaire. Expression levels of the genes were associated with the unmethylated status of related promoters (p associated with methylated RARB and BRCA1. Low intake of residual folate and cobalamin was correlated with the methylated status of RARB for subjects at 48 years of age. High dietary intake of riboflavin and pyridoxine was the only determinant of the methylated promoter of RARB at odds ratios (ORs) of 4.15 (95 % confidence interval (CI) 1.28-13.50) and 2.53 (95 % CI 1.14-3.83) in multivariate models, respectively. One-carbon nutrients most often correlated inversely with the methylation-influenced expression of RARB. Although high folate intake increased the chance of unmethylation-dependent overexpression of BRCA1 3-fold, cobalamin and methionine were inversely linked to methylation-mediated expression. Nutritional epigenomics less actively influenced RASSF1A. These findings provide new insights into and a basic understanding of the selective contributions of individual B vitamins on hypermethylation and methylation-related expression of RARB and BRCA1 in BC. Hypermethylation at promoters of RARB, BRCA1, and RASSF1A is associated with reduced transcript levels of the respective gene in primary breast cancer tissue samples. Dietary folate and cobalamin intake is inversely associated

  15. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression

    DEFF Research Database (Denmark)

    Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B

    2017-01-01

    , ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger...

  16. BRCA1-mediated repression of select X chromosome genes

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    Ropers H Hilger

    2004-09-01

    Full Text Available Abstract Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling. Significance was determined using parametric statistics with P

  17. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...... instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation...... carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...

  18. A porcine model system of BRCA1 driven breast cancer

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    Geoff eClark

    2015-08-01

    Full Text Available BRCA1 is a breast and ovarian tumor suppressor. Hereditary mutations in BRCA1 result in a predisposition to breast cancer, and BRCA1 expression is down-regulated in ~30% of sporadic cases. The function of BRCA1 remains poorly understood, but it appears to play an important role in DNA repair and the maintenance of genetic stability. Mouse models of BRCA1 deficiency have been developed in an attempt to understand the role of the gene in vivo. However, the subtle nature of BRCA1 function and the well-known discrepancies between human and murine breast cancer biology and genetics may limit the utility of mouse systems in defining the function of BRCA1 in cancer and validating the development of novel therapeutics for breast cancer. In contrast to mice, pig biological systems and cancer genetics appear to more closely resemble their human counterparts. To determine if BRCA1 inactivation in pig cells promotes their transformation and may serve as a model for the human disease, we developed an immortalized porcine breast cell line and stably inactivated BRCA1 using miRNA. The cell line developed characteristics of breast cancer stem cells and exhibited a transformed phenotype. These results validate the concept of using pigs as a model to study BRCA1 defects in breast cancer and establish the first porcine breast tumor cell line.

  19. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer.

    Science.gov (United States)

    Rosell, Rafael; Skrzypski, Marcin; Jassem, Ewa; Taron, Miquel; Bartolucci, Roberta; Sanchez, Jose Javier; Mendez, Pedro; Chaib, Imane; Perez-Roca, Laia; Szymanowska, Amelia; Rzyman, Witold; Puma, Francesco; Kobierska-Gulida, Grazyna; Farabi, Raffaele; Jassem, Jacek

    2007-11-07

    Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy

  20. BRCA1 and Oxidative Stress

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    Yong Weon Yi

    2014-04-01

    Full Text Available The breast cancer susceptibility gene 1 (BRCA1 has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.

  1. BRCA1 Reflects Myocardial Adverse Remodeling in Idiopathic Dilated Cardiomyopathy.

    Science.gov (United States)

    Nozynski, J K; Konecka-Mrowka, D; Zakliczynski, M; Zembala-Nozynska, E; Lange, D; Zembala, M

    2016-06-01

    The role of BRCA1 in chronic ischemic episodes seems to be pivotal for adverse remodeling and development of ischemic cardiomyopathy, because of its role in DNA repair and apoptosis. The aim of this study was to investigate the role of BRCA-1 in idiopathic dilated cardiomyopathy (IDCM). The study group (IDCM) comprised myocardial samples from hearts explanted before transplantation owing to IDCM in 10 males (age 44 ± 5.3 years) without clinical symptoms of ischemic heart disease. The control group consisted myocardial fragments taken from 10 male heart valve and pulmonary artery donors with diagnosed cerebral death (age 40 ± 2.3 years). BRCA1 was detected immunohistochemically with rabbit anti-BRCA1 polyclonal antibody. The intensity of BRCA1 expression was semiquantitatively assessed for cardiocytes, small vessels including capillaries, and interstitial cells. The significances between groups were estimated using the Mann-Whitney U test. All IDCM cases were positive and presented nonuniform BRCA1 expression: hypertrophied cardiocytes showed very intense staining and typical cardiomyopathic cardiocytes were stained weakly forming mosaic. Control cases showed weak-to-moderate uniform staining. Intensity of staining was significantly higher in IDCM cardiocytes, whereas small vessels and interstitial were stained similarly in both groups. IDCM adverse remodeling results in more intense but nonuniform BRCA1 expression. This phenomenon seems to reflect IDCM biology: lower BRCA1 expression in myocytes with lower anti-apoptotic and DNA damage repair activity, with the opposite in hypertrophied myofibers. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated With Estrogen Receptor-Negative Subtypes and Poor Prognosis

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    Hao Tang

    2015-03-01

    Full Text Available Both BRCA1 and Beclin 1 (BECN1 are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA (n = 1067 and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC (n = 1992. In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1 was associated with poor prognosis, and BECN1 (but not BRCA1 expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers.

  3. The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer.

    Science.gov (United States)

    Meisel, J L; Hyman, D M; Garg, K; Zhou, Q; Dao, F; Bisogna, M; Gao, J; Schultz, N D; Grisham, R N; Phillips, M; Iasonos, A; Kauff, N D; Levine, D A; Soslow, R A; Spriggs, D R

    2014-12-01

    BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemar's test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemar's test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further

  4. BRCA1 regulation on β-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer.

    Science.gov (United States)

    Sengodan, S K; Nadhan, R; Nair, R S; Hemalatha, S K; Somasundaram, V; Sushama, R R; Rajan, A; Latha, N R; Varghese, G R; Thankappan, R K; Kumar, J M; Chil, A; Anilkumar, T V; Srinivas, P

    2017-09-04

    Human chorionic gonadotropin β (β-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of β-hCG in breast cancer. We identified for the first time that β-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and β-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of β-hCG by binding to its promoter. Further, β-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of β-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since β-hCG belongs to a cysteine knot family of proteins like TGFβ and TGFβ signaling is deregulated in BRCA1 defective tumors, we checked whether β-hCG can mediate signaling through TGFβRII in BRCA1 mutated cells. We found for the first time that β-hCG can bind and phosphorylate TGFβRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on β-hCG and BRCA1 mutation promotes β-hCG mediated tumorigenesis through TGFβRII signaling. Thus inhibiting β-hCG-TGFβRII could prove an effective treatment strategy for BRCA1 mutated tumors.

  5. BRCA1 in the DNA damage response and at telomeres

    Directory of Open Access Journals (Sweden)

    Eliot Michael Rosen

    2013-06-01

    Full Text Available Abstract. Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1 account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s is (are most important for tumor suppression, nor is it clear why BRCA1 mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR, which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.

  6. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : Identification of a modifier of breast cancer risk at locus 11q22.3

    NARCIS (Netherlands)

    Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B.; Pastinen, Tomi; Droit, Arnaud; Lemacon, Audrey; Adlard, Julian; Aittomaki, Kristiina; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Azzollini, Jacopo; Bane, Anita; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J.; Bobolis, Kristie; Bonadona, Valerie; Bonanni, Bernardo; Bradbury, Angela R.; Brewer, Carole; Buecher, Bruno; Buys, Saundra; Caligo, Maria A.; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de la Hoya, Miguel; De Leeneer, Kim; Diez, Orland; Ding, Yuan Chun; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; Eccles, Diana; Eeles, Ros; Einbeigi, Zakaria; Ejlertsen, Bent; Engel, Christoph; Evans, D. Gareth; Feliubadalo, Lidia; Foretova, Lenka; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Friedman, Eitan; Frost, Debra; Ganschow, Pamela; Ganz, Patricia A.; Garber, Judy; Gayther, Simon A.; Gerdes, Anne-Marie; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Greene, Mark H.; Gronwald, Jacek; Hahnen, Eric; Hamann, Ute; Hansen, Thomas V. O.; Hart, Steven; Hays, John L.; Hogervorst, Frans B. L.; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Joseph, Vijai; Just, Walter; Kaczmarek, Katarzyna; Karlan, Beth Y.; Kets, Carolien M.; Kirk, Judy; Kriege, Mieke; Laitman, Yael; Laurent, Maite; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Loman, Niklas; Loud, Jennifer T.; Manoukian, Siranoush; Mariani, Milena; Mazoyer, Sylvie; McGuffog, Lesley; Meijers-Heijboer, Hanne E. J.; Meindl, Alfons; Miller, Austin; Montagna, Marco; Mulligan, Anna Marie; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nussbaum, Robert L.; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-Ren; Oosterwijk, Jan C.; Osorio, Ana; Papi, Laura; Park, Sue Kyung; Pedersen, Inge Sokilde; Peissel, Bernard; Segura, Pedro Perez; Peterlongo, Paolo; Phelan, Catherine M.; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Richardson, Andrea L.; Robson, Mark; Rodriguez, Gustavo C.; Rookus, Matti A.; Schmutzler, Rita Katharina; Sevenet, Nicolas; Shah, Payal D.; Singer, Christian F.; Slavin, Thomas P.; Snape, Katie; Sokolowska, Johanna; Sonderstrup, Ida Marie Heeholm; Southey, Melissa; Spurdle, Amanda B.; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Tan, Thean-Yen; Tea, Muy-Kheng; Teixeira, Manuel R.; Teule, Alex; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tung, Nadine; van den Ouweland, Ans M. W.; van der Luijt, Rob B.; van Engelen, Klaartje; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wijnen, Juul T.; Rebbeck, Timothy; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J.; Nord, Silje; Easton, Douglas F.; Antoniou, Antonis C.; Simard, Jacques

    Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and

  7. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3

    NARCIS (Netherlands)

    Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Azzollini, Jacopo; Bane, Anita; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J; Bobolis, Kristie; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caligo, Maria A; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; De la Hoya, Miguel; De Leeneer, Kim; Diez, Orland; Ding, Yuan Chun; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Eccles, Diana; Eeles, Ros; Einbeigi, Zakaria; Ejlertsen, Bent; Engel, Christoph; Gareth Evans, D; Feliubadalo, Lidia; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Friedman, Eitan; Frost, Debra; Ganschow, Pamela; Ganz, Patricia A; Garber, Judy; Gayther, Simon A; Gerdes, Anne-Marie; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hays, John L; Hogervorst, Frans B L; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Joseph, Vijai; Just, Walter; Kaczmarek, Katarzyna; Karlan, Beth Y; Kets, Carolien M; Kirk, Judy; Kriege, Mieke; Laitman, Yael; Laurent, Maïté; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Loman, Niklas; Loud, Jennifer T; Manoukian, Siranoush; Mariani, Milena; Mazoyer, Sylvie; McGuffog, Lesley; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Miller, Austin; Montagna, Marco; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Oosterwijk, Jan C; Osorio, Ana; Papi, Laura; Park, Sue Kyung; Pedersen, Inge Sokilde; Peissel, Bernard; Segura, Pedro Perez; Peterlongo, Paolo; Phelan, Catherine M; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rookus, Matti A; Schmutzler, Rita Katharina; Sevenet, Nicolas; Shah, Payal D; Singer, Christian F; Slavin, Thomas P; Snape, Katie; Sokolowska, Johanna; Sønderstrup, Ida Marie Heeholm; Southey, Melissa; Spurdle, Amanda B; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Tan, Yen; Tea, Muy-Kheng; Teixeira, Manuel R; Teulé, Alex; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tung, Nadine; van den Ouweland, Ans M W; van der Luijt, Rob B; van Engelen, Klaartje; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wijnen, Juul T; Rebbeck, Timothy; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Nord, Silje; Easton, Douglas F; Antoniou, Antonis C; Simard, Jacques

    PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1

  8. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

    NARCIS (Netherlands)

    Hamdi, Y.; Soucy, P.; Kuchenbaeker, K.B.; Pastinen, T.; Droit, A.; Lemacon, A.; Adlard, J.; Aittomaki, K.; Andrulis, I.L.; Arason, A.; Arnold, N.; Arun, B.K.; Azzollini, J.; Bane, A.; Barjhoux, L.; Barrowdale, D.; Benitez, J.; Berthet, P.; Blok, M.J.; Bobolis, K.; Bonadona, V.; Bonanni, B.; Bradbury, A.R.; Brewer, C.; Buecher, B.; Buys, S.S.; Caligo, M.A.; Chiquette, J.; Chung, W.K.; Claes, K.B.; Daly, M.B.; Damiola, F.; Davidson, R.; Hoya, M. de la; Leeneer, K. De; Diez, O.; Ding, Y.C.; Dolcetti, R.; Domchek, S.M.; Dorfling, C.M.; Eccles, D.; Eeles, R.; Einbeigi, Z.; Ejlertsen, B.; Engel, C.; Evans, D.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Foulkes, W.D.; Fountzilas, G.; Friedman, E.; Frost, D.; Ganschow, P.; Ganz, P.A.; Garber, J.; Gayther, S.A.; Gerdes, A.M.; Glendon, G.; Godwin, A.K.; Goldgar, D.E.; Greene, M.H.; Gronwald, J.; Hahnen, E.; Hamann, U.; Hansen, T.V.; Hart, S.; Hays, J.L.; Hogervorst, F.B.; Hulick, P.J.; Imyanitov, E.N.; Isaacs, C.; Izatt, L.; Jakubowska, A.; James, P.; Janavicius, R.; Jensen, U.B.; John, E.M.; Joseph, V.; Just, W.; Kaczmarek, K.; Karlan, B.Y.; Kets, C.M.; Kirk, J.; Kriege, M.; Laitman, Y.; Laurent, M.; Lazaro, C.; Leslie, G.; Lester, J.; Lesueur, F.; Liljegren, A.; Loman, N.; Loud, J.T.; Manoukian, S.; Mariani, M.; Mazoyer, S.; McGuffog, L.; Meijers-Heijboer, H.E.; Meindl, A.; et al.,

    2017-01-01

    PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1

  9. Post-transcriptional regulation of BRCA1 through its coding sequence by the miR-15/107 group of miRNAs

    Directory of Open Access Journals (Sweden)

    Kevin eQuann

    2015-07-01

    Full Text Available MicroRNAs (miRNAs are important post-transcriptional regulators of gene expression that act by degrading their RNA targets or by repressing the translation of messenger RNAs (mRNAs. Initially thought to primarily target the 3´ untranslated region (3´UTR of mRNAs, miRNAs have since been shown to also target the 5´UTR and coding sequence. In this work, we focus on the post-transcriptional regulation of the BRCA1 gene, a major tumor suppressor and regulator of double-stranded break DNA repair and show that its mRNA is targeted by many members of the miR-15/107 group at a site located within the coding sequence. Ectopic expression of these miRNAs across a panel of nine cell lines demonstrated widespread suppression of BRCA1 mRNA levels. Additionally, by cloning a putative target site from BRCA1’s amino acid coding sequence into a luciferase reporter plasmid we confirmed the direct interaction of these miRNAs with this BRCA1 target. We also examined the relationship between ectopic expression of these targeting miRNAs and BRCA1 protein levels in immortalized pancreatic epithelium (hTERT-HPNE, colorectal adenocarcinoma (HCT-116 and pancreatic adenocarcinoma (MIA PaCa-2 cell lines and found protein abundance to be variably regulated in a cell-type specific manner that was not necessarily concordant with mRNA transcript availability. Our findings reveal a previously unrecognized aspect of BRCA1’s miRNA-mediated post-transcriptional regulation, namely the targeting of its amino acid coding region by the miR-15/107 group of miRNAs. The resulting regulation is apparently complex and cell-specific, an observation that may have implications for BRCA1-mediated DNA repair across tissue types.

  10. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

    Science.gov (United States)

    Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B; Pastinen, Tomi; Droit, Arnaud; Lemaçon, Audrey; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Azzollini, Jacopo; Bane, Anita; Barjhoux, Laure; Barrowdale, Daniel; Benitez, Javier; Berthet, Pascaline; Blok, Marinus J; Bobolis, Kristie; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caligo, Maria A; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; De la Hoya, Miguel; De Leeneer, Kim; Diez, Orland; Ding, Yuan Chun; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Eccles, Diana; Eeles, Ros; Einbeigi, Zakaria; Ejlertsen, Bent; Engel, Christoph; Gareth Evans, D; Feliubadalo, Lidia; Foretova, Lenka; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Friedman, Eitan; Frost, Debra; Ganschow, Pamela; Ganz, Patricia A; Garber, Judy; Gayther, Simon A; Gerdes, Anne-Marie; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Greene, Mark H; Gronwald, Jacek; Hahnen, Eric; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hays, John L; Hogervorst, Frans B L; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Joseph, Vijai; Just, Walter; Kaczmarek, Katarzyna; Karlan, Beth Y; Kets, Carolien M; Kirk, Judy; Kriege, Mieke; Laitman, Yael; Laurent, Maïté; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Loman, Niklas; Loud, Jennifer T; Manoukian, Siranoush; Mariani, Milena; Mazoyer, Sylvie; McGuffog, Lesley; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Miller, Austin; Montagna, Marco; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Oosterwijk, Jan C; Osorio, Ana; Papi, Laura; Park, Sue Kyung; Pedersen, Inge Sokilde; Peissel, Bernard; Segura, Pedro Perez; Peterlongo, Paolo; Phelan, Catherine M; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rookus, Matti A; Schmutzler, Rita Katharina; Sevenet, Nicolas; Shah, Payal D; Singer, Christian F; Slavin, Thomas P; Snape, Katie; Sokolowska, Johanna; Sønderstrup, Ida Marie Heeholm; Southey, Melissa; Spurdle, Amanda B; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Tan, Yen; Tea, Muy-Kheng; Teixeira, Manuel R; Teulé, Alex; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tung, Nadine; van den Ouweland, Ans M W; van der Luijt, Rob B; van Engelen, Klaartje; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Wijnen, Juul T; Rebbeck, Timothy; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J; Nord, Silje; Easton, Douglas F; Antoniou, Antonis C; Simard, Jacques

    2017-01-01

    Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

  11. Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent.

    Science.gov (United States)

    Liu, Ying; Pike, Malcolm C; Wu, Nancy; Lin, Yvonne G; Mucowski, Sara; Punj, Vasu; Tang, Yuan; Yen, Hai-Yun; Stanczyk, Frank Z; Enbom, Elena; Austria, Theresa; Widschwendter, Martin; Maxson, Robert; Dubeau, Louis

    2015-01-01

    We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulatory phase of the estrous cycle and to increased basal levels of circulating estradiol. Here we show that ovarian granulosa cells from mice carrying a conditional Brca1 gene knockout express substantially higher levels of olfactory receptor mRNA than granulosa cells from wild type littermates. This led us to hypothesize that reproductive functions in mutant female mice might be more sensitive to male-derived scent than in wild type female mice. Indeed, it is well established that isolation from males leads to complete cessation of mouse estrous cycle activity while exposure to olfactory receptor ligands present in male urine leads to resumption of such activity. We found that Brca1-/- female mice rendered anovulatory by unisexual isolation resumed ovulatory activity more rapidly than their wild type littermates when exposed to bedding from cages where males had been housed. The prime mediator of this increased responsiveness appears to be the ovary and not olfactory neurons. This conclusion is supported by the fact that wild type mice in which endogenous ovaries had been replaced by Brca1-deficient ovarian transplants responded to male-derived scent more robustly than mutant mice in which ovaries had been replaced by wild type ovarian transplants. Our findings not only have important implications for our understanding of the influence of olfactory signals on reproductive functions, but also provide insights into mechanisms whereby genetic risk factors for breast and extra uterine Müllerian carcinomas may influence menstrual activity in human, which is itself an independent risk factor for these cancers.

  12. BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9.

    Science.gov (United States)

    Qin, Yunlong; Xu, Jingyao; Aysola, Kartik; Oprea, Gabriela; Reddy, Avinash; Matthews, Roland; Okoli, Joel; Cantor, Alan; Grizzle, William E; Partridge, Edward E; Reddy, E Shyam P; Landen, Charles; Rao, Veena N

    2012-01-01

    Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.

  13. BRCA1 mutations in Brazilian patients

    Directory of Open Access Journals (Sweden)

    Juliano Javert Lourenço

    2004-01-01

    Full Text Available BRCA1 mutations are known to be responsible for the majority of hereditary breast and ovarian cancers in women with early onset and a family history of the disease. In this paper we present a mutational survey conducted in 47 Brazilian patients with breast/ovarian cancer, selected based on age at diagnosis, family history, tumor laterality, and presence of breast cancer in male patients. All 22 coding exons and intron-exon junctions were sequenced. Constitutional mutations were found in seven families, consisting of one insertion (insC5382 in exon 20 (four patients, one four base-pair deletion (3450-3453delCAAG in exon 11 resulting in a premature stop codon (one patient, one transition (IVS17+2T> C in intron 17 affecting a mRNA splicing site (one patient, and a C> T transition resulting in a stop-codon (Q1135X in exon 11 (one patient. The identification of these mutations which are associated to hereditary breast and ovarian cancers will contribute to the characterization of the mutational spectrum of BRCA1 and to the improvement of genetic counseling for familial breast/ovarian cancer patients in Brazil.

  14. BRCA1 and its phosphorylation involved in caffeine-inhibitable event upstream of G2 checkpoint

    Science.gov (United States)

    Li, Ning; Zhang, Hong; Wang, Yanling; Hao, Jifang

    2010-07-01

    Caffeine, which specifically inhibits ATM/ATR kinases, efficiently abrogates the ionizing radiation (IR)-induced G2 arrest and increases the sensitivity of various tumor cells to IR. Mechanisms for the effect of caffeine remain to be elucidated. As a target of ATM/ATR kinases, BRCA1 becomes activated and phosphorylated in response to IR. Thus, in this work, we investigated the possible role of BRCA1 in the effect of caffeine on G2 checkpoint and observed how BRCA1 phosphorylation was regulated in this process. For these purposes, the BRCA1 protein level and the phosphorylation states were analyzed by Western blotting by using an antibody against BRCA1 and phospho-specific antibodies against Ser-1423 and Ser-1524 residues in cells exposed to a combination of IR and caffeine. The results showed that caffeine down-regulated IR-induced BRCA1 expression and specifically abolished BRCA1 phosphorylation of Ser-1524, which was followed by an override of G2 arrest by caffeine. In addition, the ability of BRCA1 to transactivate p21 may be required for MCF-7 but not necessary for Hela response to caffeine. These data suggest that BRCA1 may be a potential target of caffeine. BRCA1 and its phosphorylation are most likely to be involved in the caffeine-inhibitable event upstream of G2 arrest.

  15. Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer.

    Science.gov (United States)

    Hu, Hua; Zhang, Yang; Zou, Mei; Yang, Shuai; Liang, Xiao-Qiu

    2010-09-01

    Telomere dysfunction is believed to be a significant factor in carcinogenesis. To elucidate the carcinogenesis mechanism in gastric cancer, the expression of telomeric proteins and changes in telomere length were investigated during multistage carcinogenesis of gastric cancer. Tissue samples were obtained during surgical operations from the normal gastric mucosa of 10 patients, the precancerous lesions of 15 patients, the gastric cancer tissues (GC) of 20 patients, and of tumors due to gastric cancer with lymph node metastasis (GCLM) from 5 patients. The expression of TRF1, TRF2, and TIN2 proteins was measured by Western blotting, while the expression of TERT, KU70, and BRCA1 proteins was detected using the immunohistochemical method. The mean telomere length was determined by Southern blotting. Compared with normal gastric mucosa tissues, the expression of TRF1, TRF2, and TIN2 proteins was significantly higher in precancerous lesions, GC, and GCLM (P TRF2, and TIN2 proteins was significantly higher in GC and GCLM than in precancerous lesions (P TRF2, TIN2, TERT, and Ku70 proteins. Our results suggest that the over-expression of telomeric proteins, TRF1, TRF2, TIN2, TERT, and Ku70, and the transposition of the BRCA1 protein may work together to reduce the telomere length in precancerous lesions and gastric cancer, and could contribute to the multistage carcinogenesis of gastric cancer. These findings offer new insight into the mechanism of carcinogenesis in gastric cancer.

  16. BRCA1/2-negative hereditary triple-negative breast cancers exhibit BRCAness.

    Science.gov (United States)

    Domagala, Pawel; Hybiak, Jolanta; Cybulski, Cezary; Lubinski, Jan

    2017-04-01

    BRCA1/2-associated breast cancers are sensitive to poly(ADPribose) polymerase (PARP) inhibitors and platinum compounds mainly due to their deficiency in DNA repair via homologous recombination (HR). However, approximately only 15% of triple-negative breast cancers (TNBCs) are BRCA1/2-associated. TNBCs that exhibit BRCAness (a phenotype reflecting impaired HR in BRCA1/2-negative tumors) are also regarded sensitive to PARP inhibitors and platinum compounds. Thus, we hypothesized that hereditary BRCA1/2-negative TNBCs may exhibit BRCAness. To find a subset of hereditary BRCA1/2-negative TNBCs among 360 TNBCs, we first identified a group of 41 hereditary TNBCs by analyzing the family histories of the patients. Next, we tested this group for the presence of germline BRCA1/2 mutations, and finally, we compared the expression levels of 120 genes involved in HR and five other major mechanisms of DNA damage repair between BRCA1/2-associated and BRCA1/2-negative subgroups of hereditary TNBCs using real-time PCR arrays. Approximately 73% of the hereditary TNBCs were BRCA1/2-associated and 27% were BRCA1/2-negative. The expression levels of the analyzed genes showed no significant differences between these two subgroups indicating the BRCAness of the BRCA1/2-negative hereditary TNBCs and thereby distinguishing a novel subset of TNBCs as a potential target for PARP inhibitors or platinum-based therapy. The results show the significance of family history in selecting patients with TNBC for therapies directed at incompetent DNA repair (e.g., PARP inhibitors and/or platinum-based therapies) and indicate that a relatively simple strategy for broadening the target group for these modes of treatment is to identify patients with hereditary TNBCs. © 2016 UICC.

  17. The effectiveness of cucurbitacin B in BRCA1 defective breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Moltira Promkan

    Full Text Available Cucurbitacin B (CuB is one of the potential agents for long term anticancer chemoprevention. Cumulative evidences has shown that cucurbitacin B provides potent cellular biological activities such as hepatoprotective, anti-inflammatory and antimicrobial effects, but the precise mechanism of this agent is not clearly understood. We examine the biological effects on cancer cells of cucurbitacin B extracted from a Thai herb, Trichosanthes cucumerina L. The wild type (wt BRCA1, mutant BRCA1, BRCA1 knocked-down and BRCA1 overexpressed breast cancer cells were treated with the cucurbitacin B and determined for the inhibitory effects on the cell proliferation, migration, invasion, anchorage-independent growth. The gene expressions in the treated cells were analyzed for p21/(Waf1, p27(Kip1 and survivin. Our previous study revealed that loss of BRCA1 expression leads to an increase in survivin expression, which is responsible for a reduction in sensitivity to paclitaxel. In this work, we showed that cucurbitacin B obviously inhibited knocked-down and mutant BRCA1 breast cancer cells rather than the wild type BRCA1 breast cancer cells in regards to the cellular proliferation, migration, invasion and anchorage-independent growth. Furthermore, forcing the cells to overexpress wild type BRCA1 significantly reduced effectiveness of cucurbitacin B on growth inhibition of the endogenous mutant BRCA1 cells. Interestingly, cucurbitacin B promotes the expression of p21/(Waf1 and p27(Kip1 but inhibit the expression of survivin. We suggest that survivin could be an important target of cucurbitacin B in BRCA1 defective breast cancer cells.

  18. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin

    Energy Technology Data Exchange (ETDEWEB)

    Oommen, Deepu [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom); Yiannakis, Dennis [Plymouth Oncology Centre, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth PL6 8DH (United Kingdom); Jha, Awadhesh N., E-mail: a.jha@plymouth.ac.uk [School of Biological Sciences, Plymouth University, Plymouth PL4 8AA (United Kingdom)

    2016-02-15

    Highlights: • BRCA1 deficient cancer cells exhibit increased DNA damage upon auranofin treatment. • Auranofin induces apoptosis in BRCA1 deficient cancer cells despite the activation of Nrf2. • Antioxidant protects BRCA1 deficient cancer cells from auranofin. - Abstract: Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2—related factor 2 (Nrf2) via direct protein–protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

  19. BRCA1 and BRCA2 Mutations

    Science.gov (United States)

    patient education Fact Sheet PFS007: BRCA1 and BRCA2 Mutations OCTOBER 2017 BRCA1 and BRCA2 Mutations Cancer is caused by several different factors. A ... parent to child. Changes in genes are called mutations . Hereditary breast and ovarian cancer (HBOC) syndrome is ...

  20. BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number.

    Science.gov (United States)

    Starita, Lea M; Machida, Yuka; Sankaran, Satish; Elias, Joshua E; Griffin, Karen; Schlegel, Brian P; Gygi, Steven P; Parvin, Jeffrey D

    2004-10-01

    Proper centrosome duplication and spindle formation are crucial for prevention of chromosomal instability, and BRCA1 plays a role in this process. In this study, transient inhibition of BRCA1 function in cell lines derived from mammary tissue caused rapid amplification and fragmentation of centrosomes. Cell lines tested that were derived from nonmammary tissues did not amplify the centrosome number in this transient assay. We tested whether BRCA1 and its binding partner, BARD1, ubiquitinate centrosome proteins. Results showed that centrosome components, including gamma-tubulin, are ubiquitinated by BRCA1/BARD1 in vitro. The in vitro ubiquitination of gamma-tubulin was specific, and function of the carboxy terminus was necessary for this reaction; truncated BRCA1 did not ubiquitinate gamma-tubulin. BRCA1/BARD1 ubiquitinated lysines 48 and 344 of gamma-tubulin in vitro, and expression in cells of gamma-tubulin K48R caused a marked amplification of centrosomes. This result supports the notion that the modification of these lysines in living cells is critical in the maintenance of centrosome number. One of the key problems in understanding the biology of BRCA1 has been the identification of a specific target of BRCA1/BARD1 ubiquitination and its effect on mammary cell biology. The results of this study identify a ubiquitination target and suggest a biological impact important in the etiology of breast cancer.

  1. BRCA1-Dependent Ubiquitination of γ-Tubulin Regulates Centrosome Number

    Science.gov (United States)

    Starita, Lea M.; Machida, Yuka; Sankaran, Satish; Elias, Joshua E.; Griffin, Karen; Schlegel, Brian P.; Gygi, Steven P.; Parvin, Jeffrey D.

    2004-01-01

    Proper centrosome duplication and spindle formation are crucial for prevention of chromosomal instability, and BRCA1 plays a role in this process. In this study, transient inhibition of BRCA1 function in cell lines derived from mammary tissue caused rapid amplification and fragmentation of centrosomes. Cell lines tested that were derived from nonmammary tissues did not amplify the centrosome number in this transient assay. We tested whether BRCA1 and its binding partner, BARD1, ubiquitinate centrosome proteins. Results showed that centrosome components, including γ-tubulin, are ubiquitinated by BRCA1/BARD1 in vitro. The in vitro ubiquitination of γ-tubulin was specific, and function of the carboxy terminus was necessary for this reaction; truncated BRCA1 did not ubiquitinate γ-tubulin. BRCA1/BARD1 ubiquitinated lysines 48 and 344 of γ-tubulin in vitro, and expression in cells of γ-tubulin K48R caused a marked amplification of centrosomes. This result supports the notion that the modification of these lysines in living cells is critical in the maintenance of centrosome number. One of the key problems in understanding the biology of BRCA1 has been the identification of a specific target of BRCA1/BARD1 ubiquitination and its effect on mammary cell biology. The results of this study identify a ubiquitination target and suggest a biological impact important in the etiology of breast cancer. PMID:15367667

  2. Induction of ovarian leiomyosarcomas in mice by conditional inactivation of Brca1 and p53.

    Directory of Open Access Journals (Sweden)

    Bridget A Quinn

    2009-12-01

    Full Text Available Approximately one out of every ten cases of epithelial ovarian cancer (EOC is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1. In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome.We investigated the role of loss of function of BRCA1 and p53 in ovarian cancer development using mouse models with conditionally expressed alleles of Brca1 and/or p53. Our results show that ovary-specific Cre-recombinase-mediated conditional inactivation of both Brca1(LoxP/LoxP and p53(LoxP/LoxP resulted in ovarian or reproductive tract tumor formation in 54% of mice, whereas conditional inactivation of either allele alone infrequently resulted in tumors (< or =5% of mice. In mice with conditionally inactivated Brca1(LoxP/LoxP and p53(LoxP/LoxP, ovarian tumors arose after long latency with the majority exhibiting histological features consistent with high grade leiomyosarcomas lacking expression of epithelial, follicular or lymphocyte markers. In addition, tumors with conditional inactivation of both Brca1(LoxP/LoxP and p53(LoxP/LoxP exhibited greater genomic instability compared to an ovarian tumor with inactivation of only p53(LoxP/LoxP.Although conditional inactivation of both Brca1 and p53 results in ovarian tumorigenesis, our results suggest that additional genetic alterations or alternative methods for targeting epithelial cells of the ovary or fallopian tube for conditional inactivation of Brca1 and p53 are required for the development of a mouse model of Brca1-associated inherited EOC.

  3. Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways

    Science.gov (United States)

    Heublein, Sabine; Mayr, Doris; Meindl, Alfons; Angele, Martin; Gallwas, Julia; Jeschke, Udo; Ditsch, Nina

    2015-01-01

    Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38) and sporadic breast cancer (n = 86). Further, TRs were studied in MCF7 (BRCA1 wildtype) and HCC3153 (BRCA1 mutated) cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001). The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037). Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007) and overall survival (p = 0.026) while TRα positivity predicted reduced five-year survival (p = 0.030). Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients’ prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when tumors are

  4. Thyroid Hormone Receptors Predict Prognosis in BRCA1 Associated Breast Cancer in Opposing Ways.

    Directory of Open Access Journals (Sweden)

    Sabine Heublein

    Full Text Available Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38 and sporadic breast cancer (n = 86. Further, TRs were studied in MCF7 (BRCA1 wildtype and HCC3153 (BRCA1 mutated cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001. The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037. Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007 and overall survival (p = 0.026 while TRα positivity predicted reduced five-year survival (p = 0.030. Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients' prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when

  5. Localization of BRCA1 protein in human breast cancer cells.

    Science.gov (United States)

    Chambon, Monique; Nirdé, Philippe; Gleizes, Michel; Roger, Pascal; Vignon, Françoise

    2003-05-01

    There is still an ongoing debate concerning the cellular localization of BRCA1 protein in breast cancer. To address this question, we compared the localization of BRCA1 protein using several monoclonal (Ab-1) or polyclonal (C20, D20, I20) antibodies under different technical conditions on human breast cancer cell lines. We worked on the fixation and permeabilization conditions in order to preserve the morphological structures of the cells, as confirmed by transmission electron microscopy studies. As expected from the gene sequence analysis and the biochemical features, both nucleus and cytoplasmic BRCA1 protein staining were detected in cells fixed for 60 min in 4% paraformaldehyde and permeabilized with either 0.3% saponin or 0.02% Triton. In these conditions, the same results were obtained: (i) with the four antibodies tested, (ii) with several dilutions (up to tenfold) of the monoclonal antibody, and (iii) in all the tested breast cancer cell lines. In addition, we validated the functionality of these conditions by quantifying the effects of estrogens and their antagonists on the regulation of BRCA1 protein expression in the MCF7 cell line.

  6. The Role of BRCA1 in Suppressing Epithelial Mesenchymal Transition in Mammary Gland and Tumor Development

    Science.gov (United States)

    2016-11-01

    pathology and expression of CK5 and CK14 in these samples with mouse mammary tumors. We noticed that both the tumor cell morphology and expression pattern...AWARD NUMBER: W81XWH-13-1-0282 TITLE: The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor...2013 - 31-AUG-2016 4. TITLE AND SUBTITLE The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development 5a

  7. Methylation profiles of the BRCA1 promoter in hereditary and sporadic breast cancer among Han Chinese.

    Science.gov (United States)

    Pang, Da; Zhao, Yashuang; Xue, Weinan; Shan, Ming; Chen, Yanbo; Zhang, Youxue; Zhang, Guoqiang; Liu, Feng; Li, Dalin; Yang, Yanmei

    2012-09-01

    The development of breast cancer is a multistep process associated with complex changes in host gene expression patterns including inactivation of tumor suppressor genes and activation of oncogenes. Critically, hereditary predisposition plays a significant role in cancer susceptibility. However, mutation of the BRCA1 gene is found only in the minority of hereditary breast cancer, which indicates that there might be alternative, novel mechanisms contributing to inactivation of the BRCA1 gene. Studies have shown that aberrant methylation of genomic DNA plays an important role in carcinogenesis. The aim of this study was to investigate whether DNA methylation may be an alternative mechanism for the inactivation of BRCA1 as an epigenetic modification of the genome and whether hereditary breast cancer has a different BRCA1 methylation phenotype pattern than sporadic breast cancer. The pattern of CpG island methylation within the promoter region of BRCA1 was assessed by bisulfite sequencing DNA from peripheral blood cells of 72 patients with hereditary predisposition but without BRCA1 mutations and 30 sporadic breast cancer controls. The overall methylation level in patients with hereditary predisposition was significantly lower than that in the sporadic control group. However, patients with hereditary predisposition showed a significantly higher methylation susceptibility for the sites -518 when compared to controls. These results suggest that there might be different BRCA1 promoter methylation levels and patterns in sporadic and hereditary breast cancer in peripheral blood DNA. These findings may facilitate the early diagnosis of hereditary breast cancer.

  8. BRCA1 function in T lymphocytes: a cellular specificity of a different kind

    OpenAIRE

    Gardner, Kevin; Liu, Edison T

    2000-01-01

    Recent work by Mak et al demonstrates that mice carrying a T-cell-specific disruption of the brca1 gene display markedly impaired T-lymphocyte development and proliferation in the absence of any increased tendency for the formation of tumors. Interestingly, the extent of these defects was found to be highly dependent on cellular context. Contrasting the rather broad tissue expression pattern of brca1 against its exquisitely selective etiologic role in cancers of the breast and ovary, many of ...

  9. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    Science.gov (United States)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Amanda; Robson, Mark; Sherman, Mark; Mulligan, Anna Marie; Couch, Fergus J.; Engel, Christoph; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O’Malley, Frances; John, Esther M.; Janavicius, Ramunas; Tihomirova, Laima; Hansen, Thomas v O; Nielsen, Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benítez, Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schönbuchner, Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; Peshkin, Beth N.; Caldes, Trinidad; de al Hoya, Miguel; Cañadas, Carmen; Heikkinen, Tuomas; Heikkilä, Päivi; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques; Montagna, Marco; Agata, Simona; D’Andrea, Emma; Yan, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; Henriksson, Karin; Steele, Linda; Neuhausen, Susan L.; Nussbaum, Bob; Beattie, Mary; Odunsi, Kunle; Sucheston, Lara; Gayther, Simon A; Nathanson, Kate; Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers. Results There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%). Conclusions/Impact Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis. PMID:22144499

  10. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann

    2011-01-01

    Objective. It is believed that 24 - 40% of ovarian cancers have dysfunction in the BRCA1 or BRCA2 (BRCAness) genes, either due to inherited or somatic mutations or due to epigenetic inactivation. Demonstration of ovarian cancers with BRCAness is becoming important both due to the possibility of o...

  11. BRCA1 and CtIP suppress long tract gene conversion between sister chromatids

    Science.gov (United States)

    Chandramouly, Gurushankar; Kwok, Amy; Huang, Bin; Willis, Nicholas A.; Xie, Anyong; Scully, Ralph

    2013-01-01

    BRCA1 controls early steps of the synthesis-dependent strand annealing (SDSA) pathway of homologous recombination, but has no known role following Rad51-mediated synapsis. Here we show that BRCA1 influences post-synaptic homologous recombination events, controlling the balance between short- (STGC) and long-tract gene conversion (LTGC) between sister chromatids. Brca1 mutant cells reveal a bias towards LTGC that is corrected by expression of wild type but not cancer-predisposing BRCA1 alleles. The LTGC bias is enhanced by depletion of CtIP but reversed by inhibition of 53BP1, implicating DNA end resection as a contributor to the STGC/LTGC balance. The impact of BRCA1/CtIP loss on the STGC/LTGC balance is abolished when the second (non-invading) end of the break is unable to support termination of STGC by homologous pairing (“annealing”). This suggests that BRCA1/CtIP-mediated processing of the second end of the break controls the annealing step that normally terminates SDSA, thereby suppressing the error-prone LTGC outcome. PMID:23994874

  12. BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids.

    Science.gov (United States)

    Chandramouly, Gurushankar; Kwok, Amy; Huang, Bin; Willis, Nicholas A; Xie, Anyong; Scully, Ralph

    2013-01-01

    BRCA1 controls early steps of the synthesis-dependent strand annealing (SDSA) pathway of homologous recombination, but has no known role following Rad51-mediated synapsis. Here we show that BRCA1 influences post-synaptic homologous recombination events, controlling the balance between short- (STGC) and long-tract gene conversion (LTGC) between sister chromatids. Brca1 mutant cells reveal a bias towards LTGC that is corrected by expression of wild-type but not cancer-predisposing BRCA1 alleles. The LTGC bias is enhanced by depletion of CtIP but reversed by inhibition of 53BP1, implicating DNA end resection as a contributor to the STGC/LTGC balance. The impact of BRCA1/CtIP loss on the STGC/LTGC balance is abolished when the second (non-invading) end of the break is unable to support termination of STGC by homologous pairing (annealing). This suggests that BRCA1/CtIP-mediated processing of the second end of the break controls the annealing step that normally terminates SDSA, thereby suppressing the error-prone LTGC outcome.

  13. BRCA1 Mutation Leads to Deregulated Ubc9 Levels which Triggers Proliferation and Migration of Patient-Derived High Grade Serous Ovarian Cancer and Triple Negative Breast Cancer Cells.

    Science.gov (United States)

    Xu, J; Footman, A; Qin, Y; Aysola, K; Black, S; Reddy, V; Singh, K; Grizzle, W; You, S; Moellering, D; Reddy, E S; Fu, Y; Rao, V N

    2016-01-01

    Women who carry a germline mutation in BRCA1 gene typically develop triple negative breast cancers (TNBC) and high grade serous ovarian cancers (HGSOC). Previously, we reported that wild type BRCA1 proteins, unlike the disease-associated mutant BRCA1 proteins to bind the sole sumo E2-conjugating enzyme Ubc9. In this study, we have used clinically relevant cell lines with known BRCA1 mutations and report the in-vivo association of BRCA1 and Ubc9 in normal mammary epithelial cells but not in BRCA1 mutant HGSOC and TNBC cells by immunofluorescence analysis. BRCA1-mutant HGSOC/TNBC cells and ovarian tumor tissues showed increased expression of Ubc9 compared to BRCA1 reconstituted HGSOC, normal mammary epithelial cells and matched normal ovarian tissues. Knockdown of Ubc9 expression resulted in decreased proliferation and migration of BRCA1 mutant TNBC and HGSOC cells. This is the first study demonstrating the functional link between BRCA1 mutation, high Ubc9 expression and increased migration of HGSOC and TNBC cells. High Ubc9 expression due to BRCA1 mutation may trigger an early growth and transformation advantage to normal breast and ovarian epithelial cells resulting in aggressive cancers. Future work will focus on studying whether Ubc9 expression could show a positive correlation with BRCA1 linked HGSOC and basal like TNBC phenotype.

  14. Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1

    Directory of Open Access Journals (Sweden)

    Anver Miriam R

    2008-04-01

    Full Text Available Abstract Background Development of therapies for patients with BRCA1 mutations has been hampered by lack of readily available in vitro and in vivo models. We recently showed that transplantation of transgenic mammary tumors as cell suspensions into naïve recipients generates reproducible tumors with remarkable stability of gene expression profile. We examined the expression profiles of original and serially transplanted mammary tumors from Brca1 deficient mice, and tumor derived cell lines to validate their use for preclinical testing and studies of tumor biology. Methods Original tumors, serially transplanted and multiple cell lines derived from Brca1 mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers. Results Gene expression among Brca1 tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -Wnt1 models. Gene expression data segregated Brca1 tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT. Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44+/CD24-/low population that may correlate with human breast cancer stem cells. Conclusion Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among Brca1 tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCA1 deficiency.

  15. Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells.

    Science.gov (United States)

    Busschots, Steven; O'Toole, Sharon; O'Leary, John J; Stordal, Britta

    2015-08-01

    A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients. Copyright © 2014 Elsevier Inc. All rights

  16. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling

    DEFF Research Database (Denmark)

    Larsen, Martin J; Kruse, Torben A; Tan, Qihua

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants...... of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic...... tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority...

  17. BRCA 1-Mediated Histone Monoubiquitylation: Effect on Nucleosome Dynamics

    National Research Council Canada - National Science Library

    Zlatanova, Jordanka

    2008-01-01

    BRCA1, the protein product of the Breast Cancer Susceptibility Gene (BRCA1) has been implicated in multiple pathways that preserve genome stability, including cell cycle control, DNA repair, transcription, and chromatin remodeling...

  18. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 ...

  19. Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study.

    Science.gov (United States)

    Gross, Eva; van Tinteren, Harm; Li, Zhou; Raab, Sandra; Meul, Christina; Avril, Stefanie; Laddach, Nadja; Aubele, Michaela; Propping, Corinna; Gkazepis, Apostolos; Schmitt, Manfred; Meindl, Alfons; Nederlof, Petra M; Kiechle, Marion; Lips, Esther H

    2016-10-19

    Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact. One-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based "BRCA1-like" test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner. In the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087). This validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for

  20. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

    Directory of Open Access Journals (Sweden)

    Lovicu Mario

    2009-07-01

    Full Text Available Abstract Background In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Methods Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Results and Conclusion Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10% families; majority (23/35;66% of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant; b the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations; and c the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent. We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations.

  1. Analysis list: Brca1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Brca1 Blood + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.1.tsv... http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Brca...1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Brca1.Blood.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml ...

  2. Substrates of the BRCA1-dependent ubiquitin ligase.

    Science.gov (United States)

    Starita, Lea M; Parvin, Jeffrey D

    2006-02-01

    Discovering the precise function of the breast and ovarian specific tumor suppressor, BRCA1, has proven to be quite complicated. It has been determined that BRCA1, together with BARD1, comprise an E3 ubiquitin ligase. Since it is now known that BRCA1 is an enzyme, the challenge for BRCA1 research is to learn how this enzymatic activity functions in normal breast and ovarian cells in order to suppress cancerous transformation. This review will survey the known ubiquitination substrates of BRCA1 and suggest how these reactions may influence the genomic stability and proliferation of breast cells.

  3. The potential involvement of the cofactor of BRCA1 in hepatocellular carcinoma pathogenesis

    Directory of Open Access Journals (Sweden)

    Aya Youssef

    2016-08-01

    Full Text Available The cofactor of BRCA1 (COBRA1, which also refers to negative elongation factor polypeptide B (NELF-B, is a negative elongation factor (NELF subunit that has been implicated in the development and progression of several cancers. While reduced COBRA1 expression has been associated with metastatic breast cancer, COBRA1 negatively regulates the activator protein-1 (AP-1 complex, leading to the down-regulation of trefoil factor-1 (TFF1 expression in gastric cancer cell lines. The involvement of COBRA1 in hepatocellular carcinoma (HCC tumor formation and progression is not known. Here, we investigated the expression of COBRA1, the AP-1 complex, and TFF1 in several HCC cell lines; ranging from low- to high-grade HCC cell lines generated from patients with different stages of the disease. Our results showed that the COBRA1 protein was highly expressed in the low-grade HCC cell line, while significantly down-regulated in high-grade HCC cell lines. TFF1, previously regarded as a COBRA1 target gene, was only expressed in the low-grade HCC cell line and the control cells. Our results suggest that COBRA1 may play a role in HCC pathogenesis and progression. The TFF1 mRNA expression profile was uncorrelated to that of the AP-1 complex subunit proteins, which suggests the involvement of other regulatory pathways in TFF1 expression; however, this requires further study.

  4. Integrin beta 4 MRNA expression levels in bronchial asthma patients ...

    African Journals Online (AJOL)

    Serum total IgE was measured by ELISA and mRNA expression of ITGβ4 was assessed by reverse transcriptase PCR (RT-PCR) using real time PCR.. ITGβ4 mRNA expression was significantly down regulated with increased serum total IgE in patients with asthma compared to controls. Moreover, ITGβ4 expression was ...

  5. Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

    Science.gov (United States)

    Mano, Tatsuo; Nagata, Kenichi; Nonaka, Takashi; Tarutani, Airi; Imamura, Tomohiro; Hashimoto, Tadafumi; Bannai, Taro; Koshi-Mano, Kagari; Tsuchida, Takeyuki; Ohtomo, Ryo; Takahashi-Fujigasaki, Junko; Yamashita, Satoshi; Ohyagi, Yasumasa; Yamasaki, Ryo; Tsuji, Shoji; Tamaoka, Akira; Ikeuchi, Takeshi; Saido, Takaomi C; Iwatsubo, Takeshi; Ushijima, Toshikazu; Murayama, Shigeo; Hasegawa, Masato; Iwata, Atsushi

    2017-10-17

    Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases. Copyright © 2017 the Author(s). Published by PNAS.

  6. Structure-Function Of The Tumor Suppressor BRCA1

    Directory of Open Access Journals (Sweden)

    Serena L. Clark

    2012-04-01

    Full Text Available BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain mediates interactions between BRCA1 and other proteins and is responsible for the E3 ubiquitin ligase activity of BRCA1. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.

  7. The immunomodulatory effects of pegylated liposomal doxorubicin are amplified in BRCA1--deficient ovarian tumors and can be exploited to improve treatment response in a mouse model.

    Science.gov (United States)

    Mantia-Smaldone, Gina; Ronner, Lukas; Blair, Anne; Gamerman, Victoria; Morse, Christopher; Orsulic, Sandra; Rubin, Stephen; Gimotty, Phyllis; Adams, Sarah

    2014-06-01

    Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice. Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Molecular trail for the anticancer behavior of a novel copper carbohydrazone complex in BRCA1 mutated breast cancer.

    Science.gov (United States)

    Nair, Rakesh Sathish; Potti, Manoj Easwaran; Thankappan, Ratheeshkumar; Chandrika, Sivakumar Krishnankutty; Kurup, M R Prathapachandra; Srinivas, Priya

    2017-05-01

    Novel chelated metal complexes were synthesized from carbohydrazones to thiocarbohydrazones using metal-based drug designing platforms and their combination effect with Pb, a naphthaquinone were analyzed for anticancer activity in breast cancer cell lines. A panel of BRCA1 wild-type and mutated breast cancer cells: MCF-7 (BRCA1 + /ER + ), MDA-MB-231 (BRCA1 + /ERα - ), HCC-1937 (BRCA1 - /ERα - ), HCC1937/wt BRCA1, MX1 (BRCA1 - /ERα - ), and MDA-MB-436 (BRCA1 - /ERα - ) were screened for anti-cancer activity. Cu 2 (HL)(HSO 4 ) · H 2 O]SO 4  · 6 H 2 O (CS2) is the most potent anticancer agent among the copper carbohydrazone and thiocarbohydrazone complexes analyzed in this study. It can be suggested that the presence of sulphate, as pharmacologically active centre, can induce cytotoxicity more effectively when compared to chlorine, bromine, perchlorate, and methanol. This is the first report demonstrating that CS2 can bind to DNA by hindering BamH1 activity and could induce DNA double strand breaks as evidenced by γ-H2AX expression. In addition to this, CS2 could also act as a Topo II inhibitor at a much lower concentration than etoposide and induce apoptosis, making it a potent anticancer agent. In combination with Pb, a potent ROS inducer, CS2 could induce synergistic anti-cancer activity in HR/ BRCA1 defective breast cancer cells. This is the first study reporting the mechanism involved in the induction of apoptosis for a metal chelated copper carbohydrazone complex and its combination effects with Pb in HR defective, BRCA1 mutated breast cancer cells. © 2017 Wiley Periodicals, Inc.

  9. Phytochrome B mRNA expression enhances biomass yield and ...

    African Journals Online (AJOL)

    The present study shows successful transformation and mRNA expression in Phytochrome B transformed CIM 482 cotton plants. Transgenic cotton plants expressing Phytochrome B mRNA have showed more than two times increase in relative leaf growth rate (RLGR) and photosynthetic rate, more than one time increase in ...

  10. Overexpression of a protein fragment of RNA helicase A causes inhibition of endogenous BRCA1 function and defects in ploidy and cytokinesis in mammary epithelial cells.

    Science.gov (United States)

    Schlegel, Brian P; Starita, Lea M; Parvin, Jeffrey D

    2003-02-20

    The breast- and ovarian-specific tumor suppressor, BRCA1, has been implicated to function in many nuclear processes, including DNA damage repair, recombination, transcription, ubiquitination, cell cycle checkpoint enforcement, and centrosome regulation. Utilizing a previously described interaction between BRCA1 and RNA helicase A (RHA), we have developed a dominant-negative approach to block BRCA1 function in human breast epithelial cells. Overexpression of a truncated RHA peptide that can bind to the BRCA1 carboxy-terminus prevents normal BRCA1 function, such as BRCA1 association with nuclear foci following DNA damage. Overexpression of this dominant-negative protein induces pleomorphic nuclei, aberrant mitoses with extra centrosomes, and tetraploidy. This model system allows us to observe changes to mammary epithelial cells that occur acutely following loss of BRCA1 function. Furthermore, inhibition of BRCA1 via overexpressing the RHA fragment coincides with a reduction in PARP-1 protein expression, suggesting a possible mechanism for BRCA1 in the maintenance of genomic integrity.

  11. Role of BRCA1 in Controlling Mitotic Arrest in Ovarian Cystadenoma Cells

    Science.gov (United States)

    Yu, Vanessa M.; Marion, Christine M.; Austria, Theresa M.; Yeh, Jennifer; Schönthal, Axel H.; Dubeau, Louis

    2011-01-01

    Cancers that develop in BRCA1 mutation carriers are usually near tetraploid/polyploid. This led us to hypothesize that BRCA1 controls the mitotic checkpoint complex, as loss of such control could lead to mitotic errors resulting in tetraploidy/polyploidy with subsequent aneuploidy. We used an in vitro system mimicking pre-malignant conditions, consisting of cell strains derived from the benign counterparts of serous ovarian carcinomas (cystadenomas) and expressing SV40 large T antigen, conferring the equivalent of a p53 mutation. We previously showed that such cells undergo one or several doublings of their DNA content as they age in culture and approach the phenomenon of in vitro crisis. Here we show that such increase in DNA content reflects a cell cycle arrest possibly at the anaphase promoting complex, as evidenced by decreased BrdU incorporation and increased expression of the mitotic checkpoint complex. Down-regulation of BRCA1 in cells undergoing crisis leads to activation of the anaphase promoting complex and resumption of growth kinetics similar to those seen in cells before they reach crisis. Cells recovering from crisis after BRCA1 down-regulation become multinucleated, suggesting that reduced BRCA1 expression may lead to initiation of a new cell cycle without completion of cytokinesis. This is the first demonstration that BRCA1 controls a physiological arrest at the M phase apart from its established role in DNA damage response, a role that could represent an important mechanism for acquisition of aneuploidy during tumor development. This may be particularly relevant to cancers that have a near tetraploid/polyploid number of chromosomes. PMID:21792894

  12. BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.

    Science.gov (United States)

    Derks-Smeets, I A P; van Tilborg, T C; van Montfoort, A; Smits, L; Torrance, H L; Meijer-Hoogeveen, M; Broekmans, F; Dreesen, J C F M; Paulussen, A D C; Tjan-Heijnen, V C G; Homminga, I; van den Berg, M M J; Ausems, M G E M; de Rycke, M; de Die-Smulders, C E M; Verpoest, W; van Golde, R

    2017-08-22

    accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

  13. Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.

    Science.gov (United States)

    de la Hoya, Miguel; Soukarieh, Omar; López-Perolio, Irene; Vega, Ana; Walker, Logan C; van Ierland, Yvette; Baralle, Diana; Santamariña, Marta; Lattimore, Vanessa; Wijnen, Juul; Whiley, Philip; Blanco, Ana; Raponi, Michela; Hauke, Jan; Wappenschmidt, Barbara; Becker, Alexandra; Hansen, Thomas V O; Behar, Raquel; Investigators, KConFaB; Niederacher, Diether; Arnold, Norbert; Dworniczak, Bernd; Steinemann, Doris; Faust, Ulrike; Rubinstein, Wendy; Hulick, Peter J; Houdayer, Claude; Caputo, Sandrine M; Castera, Laurent; Pesaran, Tina; Chao, Elizabeth; Brewer, Carole; Southey, Melissa C; van Asperen, Christi J; Singer, Christian F; Sullivan, Jan; Poplawski, Nicola; Mai, Phuong; Peto, Julian; Johnson, Nichola; Burwinkel, Barbara; Surowy, Harald; Bojesen, Stig E; Flyger, Henrik; Lindblom, Annika; Margolin, Sara; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Galastri, Laura; Olson, Janet E; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Andrulis, Irene L; Glendon, Gord; Hall, Per; Czene, Kamila; Blows, Fiona; Shah, Mitul; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; McGuffog, Lesley; Bolla, Manjeet K; Antoniou, Antonis C; Easton, Douglas F; Couch, Fergus J; Tavtigian, Sean; Vreeswijk, Maaike P; Parsons, Michael; Meeks, Huong D; Martins, Alexandra; Goldgar, David E; Spurdle, Amanda B

    2016-06-01

    A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10(-8) Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. BRCA1 mutation site may be linked with nuclear DNA ploidy in BRCA1-mutated ovarian carcinomas.

    Science.gov (United States)

    Aghmesheh, Morteza; Saxena, Akshat; Niknam, Farshid

    2015-06-01

    BRCA1 has a role in maintaining normal nuclear DNA content during cell division and its inactivation may result in DNA aneuploidy and cancer progression. BRCA1-linked breast cancers are more aneuploid and have a worse prognosis, but this has not been elucidated in ovarian cancers. This study explores the potential difference in ploidy status between BRCA1-mutated and sporadic ovarian carcinomas. It also explores the potential association between BRCA1 mutation site and DNA ploidy status. This study compared DNA ploidy status of tumor blocks from 23 BRCA1-mutated ovarian carcinomas with that of 23 sporadic ovarian carcinomas matched for histologic subtype, patient age, stage and grade. DNA content of the nuclei was measured by Feulgen-Schiff staining followed by image cytometry and compared. BRCA1-linked tumors with a stop codon closer to the N-terminal (between 1 and 500 aa; 6/6, 100%) had a significantly higher frequency of nondiploidy compared with those with stop codon above 500 aa (7/12, 58%) (P = 0.033). A diploid peak was detected in 28% of BRCA1-mutated ovarian cancers and in 33% of sporadic ovarian cancers. The present study concluded that ovarian tumors with mutations closer to the N-terminal of BRCA1 may have a higher risk of DNA aneuploidy. There is no significant difference between BRCA1-mutated and sporadic ovarian carcinomas with respect to the DNA content. © 2014 Wiley Publishing Asia Pty Ltd.

  15. BRCA1 promoter methylation of normal breast epithelial cells as a possible precursor for BRCA1-methylated breast cancer

    Science.gov (United States)

    Otani, Yoko; Miyake, Tomohiro; Kagara, Naofumi; Shimoda, Masafumi; Naoi, Yasuto; Maruyama, Naomi; Shimomura, Atsuhi; Shimazu, Kenzo; Kim, Seung Jin; Noguchi, Shinzaburo

    2014-01-01

    The breast cancer susceptibility gene 1 (BRCA1) and glutathione S-transferase P1 (GSTP1) promoters are reportedly often methylated in breast cancer tissues. Their methylation status in surrounding normal breast tissues has not been examined thoroughly although this may well be important for a better understanding of breast carcinogenesis. In this study, BRCA1 and GSTP1 promoter methylation was examined by methylation-specific PCR assay. Patients with BRCA1-methylated (n = 15) or BRCA1-unmethylated (n = 15) tumors and those with GSTP1-methylated (n = 9) or GSTP1-unmethylated (n = 11) tumors were included in the present study. Methylation status of manually micro-dissected normal epithelial cells from the formalin-fixed paraffin-embedded sections of normal breast tissues adjacent to and distant from the tumors was examined at multiple sites (n = 1–5). Of the 15 patients with BRCA1-methylated tumors, 9 harbored BRCA1 promoter methylation in at least one site of the normal breast tissues. However, no BRCA1 promoter methylation was observed at any site of the normal tissues of the 15 patients with BRCA1-unmethylated tumors. No GSTP1 promoter methylation was observed in the normal tissues regardless of the methylation status of the tumors. The presence of BRCA1 promoter methylation in the normal tissues was confirmed in the epithelial cells enriched with the magnetic-activated cell sorting method. Our findings suggest that a small proportion of normal breast epithelial cells with BRCA1 promoter methylation can be precursor cells from which BRCA1-methylated breast tumors may originate. This does not apply to GSTP1 promoter methylation. PMID:25155055

  16. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, Thomas; Ejlertsen, Bent; Albrechtsen, Anders

    2009-01-01

    exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight......Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit...

  17. Analysis list: BRCA1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available BRCA1 Blood,Breast,Digestive tract,Liver,Pluripotent stem cell,Uterus + hg19 http://dbarc...hive.biosciencedbc.jp/kyushu-u/hg19/target/BRCA1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BRC...A1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BRCA1.10.tsv http://dbarchive.bio...sciencedbc.jp/kyushu-u/hg19/colo/BRCA1.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BRC...A1.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BRCA1.Digestive_tract.tsv,http://dbarc

  18. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, T.v.O.; Ejlertsen, B.; Albrechtsen, Anders

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight...... of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit...

  19. Two novel variants in the 3?UTR of the BRCA1 gene in familial breast and/or ovarian cancer

    OpenAIRE

    2010-01-01

    Abstract For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3? untranslated region (3?UTR) are implicated in cancer. Genetic changes in the 3?UTR of several genes were reported to be associated with higher susceptibility to particular tumor types. The aim of this study was to analyze the BRCA1 3?UTR in patients tested negativ...

  20. The BRCA1 variant p.Ser36Tyr abrogates BRCA1 protein function and potentially confers a moderate risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Charita M Christou

    Full Text Available The identification of variants of unknown clinical significance (VUS in the BRCA1 gene complicates genetic counselling and causes additional anxiety to carriers. In silico approaches currently used for VUS pathogenicity assessment are predictive and often produce conflicting data. Furthermore, functional assays are either domain or function specific, thus they do not examine the entire spectrum of BRCA1 functions and interpretation of individual assay results can be misleading. PolyPhen algorithm predicted that the BRCA1 p.Ser36Tyr VUS identified in the Cypriot population was damaging, whereas Align-GVGD predicted that it was possibly of no significance. In addition the BRCA1 p.Ser36Tyr variant was found to be associated with increased risk (OR = 3.47, 95% CI 1.13-10.67, P = 0.02 in a single case-control series of 1174 cases and 1109 controls. We describe a cellular system for examining the function of exogenous full-length BRCA1 and for classifying VUS. We achieved strong protein expression of full-length BRCA1 in transiently transfected HEK293T cells. The p.Ser36Tyr VUS exhibited low protein expression similar to the known pathogenic variant p.Cys61Gly. Co-precipitation analysis further demonstrated that it has a reduced ability to interact with BARD1. Further, co-precipitation analysis of nuclear and cytosolic extracts as well as immunofluorescence studies showed that a high proportion of the p.Ser36Tyr variant is withheld in the cytoplasm contrary to wild type protein. In addition the ability of p.Ser36Tyr to co-localize with conjugated ubiquitin foci in the nuclei of S-phase synchronized cells following genotoxic stress with hydroxyurea is impaired at more pronounced levels than that of the p.Cys61Gly pathogenic variant. The p.Ser36Tyr variant demonstrates abrogated function, and based on epidemiological, genetic, and clinical data we conclude that the p.Ser36Tyr variant is probably associated with a moderate breast cancer risk.

  1. Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis

    DEFF Research Database (Denmark)

    Krakauer, Martin; Sorensen, P; Khademi, M

    2008-01-01

    volunteers served to confirm initial findings. mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR). RESULTS: We found elevated expression of interleukin (IL)-23 and IL-10 in untreated MS patients. IFN-beta therapy increased IL-10 and decreased IL-23 expression independently...... of the regulatory cytokine IL-10. The elevated IL-23 mRNA levels in MS patients are noteworthy in view of the newly discovered IL-23-driven Th17 T-cell subset, which is crucial in animal models of MS. Since IFN-beta therapy resulted in decreased IL-23 mRNA levels, the Th17 axis could be another target of IFN...

  2. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II.

    Science.gov (United States)

    Starita, Lea M; Horwitz, Andrew A; Keogh, Michael-Christopher; Ishioka, Chikashi; Parvin, Jeffrey D; Chiba, Natsuko

    2005-07-01

    The breast- and ovarian-specific tumor suppressor BRCA1, when associated with BARD1, is an ubiquitin ligase. We have shown here that this heterodimer ubiquitinates a hyperphosphorylated form of Rpb1, the largest subunit of RNA polymerase II. Two major phosphorylation sites have been identified in the Rpb1 carboxyl terminal domain, serine 2 (Ser-2) or serine 5 (Ser-5) of the YSPTSPS heptapeptide repeat. Only the Ser-5 hyperphosphorylated form is ubiquitinated by BRCA1/BARD1. Overexpression of BRCA1 in cells stimulated the DNA damage-induced ubiquitination of Rpb1. Similar to the in vitro reaction, the stimulation of Rpb1 ubiquitination by BRCA1 in cells occurred only on those molecules hyperphosphorylated on Ser-5 of the heptapeptide repeat. In vitro, the carboxyl terminus of BRCA1 (amino acids 501-1863) was dispensable for the ubiquitination of hyperphosphorylated Rpb1. In cells, however, efficient Rpb1 ubiquitination required the carboxyl terminus of BRCA1, suggesting that interactions mediated by this region were essential in the complex milieu of the nucleus. These results link the BRCA1-dependent ubiquitination of the polymerase with DNA damage.

  3. Function of BRCA1 at a DNA Replication Origin

    National Research Council Canada - National Science Library

    Lieberman, Paul

    2004-01-01

    ... and allow efficient repair of damaged DNA. In this proposal, we present preliminary data that BRCA1 functions in a DNA checkpoint response for the origin of Epstein-Barr Virus DNA replication (Ori P...

  4. Structural Basis for BRCA1 Function in Breast Cancer

    National Research Council Canada - National Science Library

    Ladias, John A

    2005-01-01

    The Breast Cancer Susceptibility gene 1 (BRCA1) encodes an 1863-amino acid protein that has important functions in cell cycle checkpoint control and DNA repair and plays a central role in the pathogenesis of breast cancer...

  5. Association between VDAC1 mRNA expression and intracellular ...

    African Journals Online (AJOL)

    One way in which xenobiotics induce apoptotic cell death is to alter the selective permeability of the intracellular voltage-dependent anion channel (VDAC1) in the mitochondrial membrane. In this study, we explored the association between VDAC1 mRNA expression and mitochondrial function during hexavalent chromium ...

  6. Cytokine mRNA expression during experimental corneal allograft rejection

    NARCIS (Netherlands)

    Torres, P. F.; de Vos, A. F.; van der Gaag, R.; Martins, B.; Kijlstra, A.

    1996-01-01

    Allograft rejection is the main cause of corneal graft failure. T lymphocytes and macrophages have been implied to be involved in corneal rejection, but little is known about the molecular mechanism in this process. In this study, cytokine mRNA expression in the cornea was analysed during

  7. Cloning and mRNA expression pattern analysis under low ...

    African Journals Online (AJOL)

    This research cloned endochitinase-antifreeze protein precursor (EAPP) gene of Dong-mu 70 rye (Secale cereale) by designing special primers according to Genbank's EAPP gene sequence, and analyzing the influence of low temperature stress on the expression of mRNA with RT-PCR. The results indicated that the ...

  8. Cloning and mRNA expression pattern analysis under low ...

    African Journals Online (AJOL)

    Jane

    2011-07-13

    Jul 13, 2011 ... This research cloned endochitinase-antifreeze protein precursor (EAPP) gene of Dong-mu 70 rye. (Secale cereale) by designing special primers according to Genbank's EAPP gene sequence, and analyzing the influence of low temperature stress on the expression of mRNA with RT-PCR. The results.

  9. Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution.

    Directory of Open Access Journals (Sweden)

    Prashant Kumar

    Full Text Available Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.

  10. LOS GENES BRCA1 y BRCA2. ESTUDIO MOLECULAR

    Directory of Open Access Journals (Sweden)

    N. Alonso

    2006-11-01

    Full Text Available RESUMENEn los últimos años, se realizaron numerosos estudios para establecer la predisposición hereditaria al cáncer y las alteraciones mutacionales a nivel de genes susceptibles de originar cáncer de mama y ovario. En 1994 se identificaron los genes BRCA1 (Breast Cancer Gene 1 y BRCA2 (Breast Cancer Gene 2 como susceptibles de cáncer de mama y ovario. En la actualidad se sabe que las mutaciones en BRCA1 y BRCA2 están lejos de explicar la totalidad de los casos de cáncer de mama y/o ovario, y a pesar de que se postulan alteraciones mutacionales en otros genes como CHEK2, TP53 y PTEN, el BRCA1 y BRCA2, siguen teniendo su importancia y utilidad en la valoración del riesgo de predisposición hereditaria. Aunque las cifras son variables según los distintos estudios y autores, se trata en cualquier caso de porcentajes importantes. Entre el 15 y el 85% de las mujeres portadoras de mutación BRCA 1 o BRCA 2 tienen riesgo de desarrollar un cáncer de mama y entre un 10 y 60% de desarrollar un cáncer de ovario. ABSTRACT:In the last years, numerous studies were made to establish the hereditary predisposition to the cancer and the mutationals alterations at level of genes susceptible to originate breast and ovarian cancers. In 1994 genes BRCA1 (Breast Cancer Gene 1 and BRCA2 were identified (Breast Cancer Gene 2 as susceptible of both of breast and ovarian cancers. At the present time, it is knows that the mutations in BRCA 1 and BRCA 2 are far from explaining the totality of the cases of breast cancer and/or ovary, and although mutationals alterations in other genes like CHEK2, TP53 and PTEN, the BRCA1 and BRCA2 are postulated, they continue having his importance and utility in the valuation of the risk of hereditary predisposition. Correlations between both BRCA1 and BRCA2 levels with tumour grade metastasis and prognostic accuracy. Between 15 and 85% of the carrying women of mutation BRCA 1 or BRCA 2 have risk of developing a cancer of breast

  11. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, Charlene; Zhang, Junran, E-mail: Junran.zhang@case.edu

    2015-10-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.

  12. HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b.

    Directory of Open Access Journals (Sweden)

    Ilaria Lepore

    Full Text Available Over the past years BARD1 (BRCA1-associated RING domain 1 has been considered as both a BRCA1 (BReast Cancer susceptibility gene 1, early onset interactor and tumor suppressor gene mutated in breast and ovarian cancers. Despite its role as a stable heterodimer with BRCA1, increasing evidence indicates that BARD1 also has BRCA1-independent oncogenic functions. Here, we investigate BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s and microRNAs. We show that the HDACi (histone deacetylase inhibitor Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR-19b expression levels. Moreover, we identify a specific BARD1 isoform, which might act as tumor diagnostic and prognostic markers.

  13. BRCA1 interaction of centrosomal protein Nlp is required for successful mitotic progression.

    Science.gov (United States)

    Jin, Shunqian; Gao, Hua; Mazzacurati, Lucia; Wang, Yang; Fan, Wenhong; Chen, Qiang; Yu, Wei; Wang, Mingrong; Zhu, Xueliang; Zhang, Chuanmao; Zhan, Qimin

    2009-08-21

    Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability.

  14. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants.

    Science.gov (United States)

    Starita, Lea M; Young, David L; Islam, Muhtadi; Kitzman, Jacob O; Gullingsrud, Justin; Hause, Ronald J; Fowler, Douglas M; Parvin, Jeffrey D; Shendure, Jay; Fields, Stanley

    2015-06-01

    Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological-effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing. Copyright © 2015 by the Genetics Society of America.

  15. Generation of induced pluripotent stem cell (iPSC) line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene.

    Science.gov (United States)

    Griscelli, Frank; Oudrhiri, Noufissa; Feraud, Olivier; Divers, Dominique; Portier, Lucie; Turhan, Ali G; Bennaceur Griscelli, Annelise

    2017-10-01

    BRCA1 germline mutation confers hereditary predisposition for breast and ovarian cancer. To understand the physiopathology of mammary and ovarian epithelial cancer transformation, and to identify early driver molecular events, we have generated an iPSC line from a patient carrying a germline exon 17 deletion in BRCA1 gene (BRAC1Ex17 iPSC) in a high-risk family context. Blood cells were reprogrammed used non-integrative virus of Sendaï. The BRCA1-deleted iPSC had normal karyotype, harboured a deletion in the exon 17 of the BRCA1 gene, expressed pluripotent hallmarks and had the differentiation capacity into the three germ layers. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Generation of induced pluripotent stem cell (iPSC line from a patient with triple negative breast cancer with hereditary exon 17 deletion of BRCA1 gene

    Directory of Open Access Journals (Sweden)

    Frank Griscelli

    2017-10-01

    Full Text Available BRCA1 germline mutation confers hereditary predisposition for breast and ovarian cancer. To understand the physiopathology of mammary and ovarian epithelial cancer transformation, and to identify early driver molecular events, we have generated an iPSC line from a patient carrying a germline exon 17 deletion in BRCA1 gene (BRAC1Ex17 iPSC in a high-risk family context. Blood cells were reprogrammed used non-integrative virus of Sendaï. The BRCA1-deleted iPSC had normal karyotype, harboured a deletion in the exon 17 of the BRCA1 gene, expressed pluripotent hallmarks and had the differentiation capacity into the three germ layers.

  17. Mutation screening of MIR146A/B and BRCA1/2 3'-UTRs in the GENESIS study.

    Science.gov (United States)

    Garcia, Amandine I; Buisson, Monique; Damiola, Francesca; Tessereau, Chloé; Barjhoux, Laure; Verny-Pierre, Carole; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Caron, Olivier; Gautier-Villars, Marion; Coupier, Isabelle; Buecher, Bruno; Vennin, Philippe; Belotti, Muriel; Lortholary, Alain; Gesta, Paul; Dugast, Catherine; Noguès, Catherine; Fricker, Jean-Pierre; Faivre, Laurence; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M; Mazoyer, Sylvie

    2016-08-01

    Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3'- untranslated regions (3'-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3'-UTR and one in BRCA2 3'-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3'-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3'-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

  18. LOS GENES BRCA1 y BRCA2. ESTUDIO MOLECULAR

    OpenAIRE

    N. Alonso; R. García Iglesias; L. Martín Rodríguez; J.A. Minguéz Pargas; I. Gonzalez Blanco; A. San Miguel; F.J. Martín Gil

    2006-01-01

    RESUMENEn los últimos años, se realizaron numerosos estudios para establecer la predisposición hereditaria al cáncer y las alteraciones mutacionales a nivel de genes susceptibles de originar cáncer de mama y ovario. En 1994 se identificaron los genes BRCA1 (Breast Cancer Gene 1) y BRCA2 (Breast Cancer Gene 2) como susceptibles de cáncer de mama y ovario. En la actualidad se sabe que las mutaciones en BRCA1 y BRCA2 están lejos de explicar la totalidad de los casos de cáncer de mama y/o ovario,...

  19. The {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer.

    LENUS (Irish Health Repository)

    Buckley, Niamh E

    2011-03-01

    Little is known about the origin of basal-like breast cancers, an aggressive disease that is highly similar to BRCA1-mutant breast cancers. p63 family proteins that are structurally related to the p53 suppressor protein are known to function in stem cell regulation and stratified epithelia development in multiple tissues, and p63 expression may be a marker of basal-like breast cancers. Here we report that ΔNp63 isoforms of p63 are transcriptional targets for positive regulation by BRCA1. Our analyses of breast cancer tissue microarrays and BRCA1-modulated breast cancer cell lines do not support earlier reports that p63 is a marker of basal-like or BRCA1 mutant cancers. Nevertheless, we found that BRCA1 interacts with the specific p63 isoform ΔNp63γ along with transcription factor isoforms AP-2α and AP-2γ. BRCA1 required ΔNp63γ and AP-2γ to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the ΔNp63 isoforms. In mammary stem\\/progenitor cells, siRNA-mediated knockdown of ΔNp63 expression resulted in genomic instability, increased cell proliferation, loss of DNA damage checkpoint control, and impaired growth control. Together, our findings establish that transcriptional upregulation of ΔNp63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-ΔNp63 signaling are key events in the pathogenesis of basal-like breast cancer. Cancer Res; 71(5); 1933-44. ©2011 AACR.

  20. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms

    NARCIS (Netherlands)

    Schouten, Philip C.; Grigoriadis, Anita; Kuilman, Thomas; Mirza, Hasan; Watkins, Johnathan A.; Cooke, Saskia A.; van Dyk, Ewald; Severson, Tesa M.; Rueda, Oscar M.; Hoogstraat, Marlous; Verhagen, Caroline V. M.; Natrajan, Rachael; Chin, Suet-Feung; Lips, Esther H.; Kruizinga, Janneke; Velds, Arno; Nieuwland, Marja; Kerkhoven, Ron M.; Krijgsman, Oscar; Vens, Conchita; Peeper, Daniel; Nederlof, Petra M.; Caldas, Carlos; Tutt, Andrew N.; Wessels, Lodewyk F.; Linn, Sabine C.

    Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively.

  1. Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-beta treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression

    DEFF Research Database (Denmark)

    Krakauer, M.; Sorensen, P.; Khademi, M.

    2008-01-01

    volunteers served to confirm initial findings. mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR). RESULTS: We found elevated expression of interleukin (IL)-23 and IL-10 in untreated MS patients. IFN-beta therapy increased IL-10 and decreased IL-23 expression independently...... of the regulatory cytokine IL-10. The elevated IL-23 mRNA levels in MS patients are noteworthy in view of the newly discovered IL-23-driven Th17 T-cell subset, which is crucial in animal models of MS. Since IFN-beta therapy resulted in decreased IL-23 mRNA levels, the Th17 axis could be another target of IFN...

  2. Methylation of the tumor suppressor protein, BRCA1, influences its transcriptional cofactor function.

    Directory of Open Access Journals (Sweden)

    Irene Guendel

    Full Text Available BACKGROUND: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription. Many cellular events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modification with activating or repressive effects. METHODS/PRINCIPAL FINDINGS: Here we demonstrate for the first time that BRCA1 is methylated both in breast cancer cell lines and breast cancer tumor samples at arginine and lysine residues through immunoprecipitation and western blot analysis. Arginine methylation by PRMT1 was observed in vitro and the region of BRCA1 504-802 shown to be highly methylated. PRMT1 was detected in complex with BRCA1 504-802 through in vitro binding assays and co-immunoprecipitated with BRCA1. Inhibition of methylation resulted in decreased BRCA1 methylation and alteration of BRCA1 binding to promoters in vivo as shown through chromatin immunoprecipitation assays. Knockdown of PRMT1 also resulted in increased BRCA1 binding to particular promoters in vivo. Finally, following methylation inhibition, Sp1 was found to preferentially associate with hypo-methylated BRCA1 and STAT1 was found to preferentially associate with hyper-methylated BRCA1. CONCLUSIONS/SIGNIFICANCE: These results suggest that methylation may influence either the ability of BRCA1 to bind to specific promoters or protein-protein interactions which alters the recruitment of BRCA1 to these promoters. Thus, given the importance of BRCA1 to genomic stability, methylation of BRCA1 may ultimately affect the tumor suppressor ability of BRCA1.

  3. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Directory of Open Access Journals (Sweden)

    Dirce Maria Carraro

    Full Text Available Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22% [7 in BRCA1 (13%, 4 in BRCA2 (7% and one in TP53 (2% gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes. Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  4. Screening for genomic rearrangements at BRCA1 locus in Iranian ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 92; Issue 1. Screening for genomic rearrangements at BRCA1 locus in Iranian women with breast cancer using multiplex ligation-dependent probe amplification. Vahid R. Yassaee Babak Emamalizadeh Mir Davood Omrani. Research Note Volume 92 Issue 1 April 2013 pp 131- ...

  5. Identification of novel intronic BRCA1 variants of uncertain ...

    Indian Academy of Sciences (India)

    in a Thai hereditary breast cancer family. Adisorn Ratanaphan, Pornpen Panomwan, Bhutorn Canyuk and Tanaphon Maipang. J. Genet. 90, 327–331. Table 1. Oligodeoxyribonucleotide primers used for PCR amplification of BRCA1 exon–intron 7 boundary sequences. Primers. Nucleotide position. Primer sequence (5 –3 ).

  6. Identification of novel intronic BRCA1 variants of uncertain ...

    Indian Academy of Sciences (India)

    Identification of novel intronic BRCA1 variants of uncertain significance in a Thai hereditary breast cancer family ... Faculty of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Laboratory of Pharmaceutical Biotechnology, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand; Faculty of ...

  7. "Ring-fencing" BRCA1 tumor suppressor activity.

    Science.gov (United States)

    Patel, Ketan J; Crossan, Gerry P; Hodskinson, Michael R G

    2011-12-13

    BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Nilbert, Mef; Petersen, Janne

    2016-01-01

    Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk...... in mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk...... was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G...

  9. BRCA1 and BRCA2 germline mutation analysis among Indian ...

    Indian Academy of Sciences (India)

    Prakash

    , Gupta V, Shukla N K, Deo S S and Das B C 2004. Novel germline mutations in breast cancer susceptibility genes. BRCA1, BRCA2 and p53 gene in breast cancer patients from. India; Breast Cancer Res. Treat. 88 177–186. Ikeda N, Miyoshi Y, ...

  10. Proteomic Profiling of β-hCG-Induced Spheres in BRCA1 Defective Triple Negative Breast Cancer Cells.

    Science.gov (United States)

    Sengodan, Satheesh Kumar; Rajan, Arathi; Hemalatha, Sreelatha Krishnakumar; Nadhan, Revathy; Jaleel, Abdul; Srinivas, Priya

    2018-01-05

    Previously, we identified that β-hCG is expressed by BRCA1 mutated but not wild type breast cancers in vitro/in vivo and exhibited a novel event in β-hCG overexpressing BRCA1 mutated HCC1937 cells where the cells were able to form spheres (HCC1937 β spheres) in adherent cell culture plates even in the absence of any growth factors. These spheres express stem cell and EMT markers. In the present study, we carried out the total proteomic profiling of these HCC1937 β spheres obtained from BRCA1 defective β-hCG expressing stable breast cancer cells to analyze the cell signaling pathways that are active in these cells. Functional annotation revealed proteins (164 cellular and 97 secretory) predominantly involved in oxygen binding, nucleosome assembly, cytoskeleton organization, protein folding, etc. Many of the proteins identified from HCC1937 β spheres in this study are also up regulated in breast cancers, which are directly linked with poor prognosis in human cancer samples as analyzed using TCGA data set. Survival analysis shows that β-hCG expressing cancer patients are linked with poor survival rate. Interestingly, hemoglobins were identified at both cellular and secretory level in HCC1937 β spheres and experiments after treating with ROS inducers revealed that β-hCG induces hemoglobin and protects the cancer cells during oxidative stress. Our proteomic data strongly propose β-hCG as an oncogenic molecule associated with BRCA1 mutation, and hence, targeting β-hCG could be a strategy to treat BRCA1 defective breast cancers.

  11. Expression of type XXIII collagen mRNA and protein.

    Science.gov (United States)

    Koch, Manuel; Veit, Guido; Stricker, Sigmar; Bhatt, Pinaki; Kutsch, Stefanie; Zhou, Peihong; Reinders, Elina; Hahn, Rita A; Song, Rich; Burgeson, Robert E; Gerecke, Donald R; Mundlos, Stefan; Gordon, Marion K

    2006-07-28

    Collagen XXIII is a member of the transmembranous subfamily of collagens containing a cytoplasmic domain, a membrane-spanning hydrophobic domain, and three extracellular triple helical collagenous domains interspersed with non-collagenous domains. We cloned mouse, chicken, and humanalpha1(XXIII) collagen cDNAs and showed that this non-abundant collagen has a limited tissue distribution in non-tumor tissues. Lung, cornea, brain, skin, tendon, and kidney are the major sites of expression. In contrast, five transformed cell lines were tested for collagen XXIII expression, and all expressed the mRNA. In vivo the alpha1(XXIII) mRNA is found in mature and developing organs, the latter demonstrated using stages of embryonic chick cornea and mouse embryos. Polyclonal antibodies were generated in guinea pig and rabbit and showed that collagen XXIII has a transmembranous form and a shed form. Comparison of collagen XXIII with its closest relatives in the transmembranous subfamily of collagens, types XIII and XXV, which have the same number of triple helical and non-collagenous regions, showed that there is a discontinuity in the alignment of domains but that striking similarities remain despite this.

  12. Hereditary ovarian cancer and two-compartment tumor metabolism: epithelial loss of BRCA1 induces hydrogen peroxide production, driving oxidative stress and NFκB activation in the tumor stroma.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo E; Balliet, Renee M; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary ovarian cancers. Here, we used a co-culture approach to study the metabolic effects of BRCA1-null ovarian cancer cells on adjacent tumor-associated stromal fibroblasts. Our results directly show that BRCA1-null ovarian cancer cells produce large amounts of hydrogen peroxide, which can be abolished either by administration of simple antioxidants (N-acetyl-cysteine; NAC) or by replacement of the BRCA1 gene. Thus, the BRCA1 gene normally suppresses tumor growth by functioning as an antioxidant. Importantly, hydrogen peroxide produced by BRCA1-null ovarian cancer cells induces oxidative stress and catabolic processes in adjacent stromal fibroblasts, such as autophagy, mitophagy and glycolysis, via stromal NFκB activation. Catabolism in stromal fibroblasts was also accompanied by the upregulation of MCT4 and a loss of Cav-1 expression, which are established markers of a lethal tumor microenvironment. In summary, loss of the BRCA1 tumor suppressor gene induces hydrogen peroxide production, which then leads to metabolic reprogramming of the tumor stroma, driving stromal-epithelial metabolic coupling. Our results suggest that new cancer prevention trials with antioxidants are clearly warranted in patients that harbor hereditary/familial BRCA1 mutations.

  13. Inducible Transgenic Models of BRCA1 Function

    Science.gov (United States)

    2000-10-01

    replaced by C, and H=C, U or A. Hammerhead ribozymes have been shown to effectively and selectively inhibit gene expression in bacteria, plants , cell...fulfills these criteria. In addition, this system permits early effects of trangene expression to be analyzed in normal epithelium. By permitting both the...shown). These findings suggest that rtTA trangene expression in MTB mice may demonstrate a greater degree of mammary specificity than is typically seen in

  14. The Role of BRCA1/BARD1 Heterodimers in the Mitosis-Interphase Transition

    National Research Council Canada - National Science Library

    Joukov, Vladimir

    2007-01-01

    ... and ovarian tumor suppressor BRCA1 and its hetorodimerizing partner, BARD1. Experiments using both egg extracts and cultured mammalian cells revealed a previously unknown role of BRCA1/BARD1 in the mitotic spindle assembly...

  15. Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma

    NARCIS (Netherlands)

    Majdak, EJ; Debniak, J; Milczek, T; Cornelisse, CJ; Devilee, P; Emerich, J; Jassem, J; De Bock, GH

    2005-01-01

    BACKGROUND. The clinical relevance of BRCA1/2 alterations in ovarian carcinoma patients is debatable. Our aim was to determine factors influencing the risk of recurrence and death in ovarian carcinoma patients with BRCA pathogenic and unclassified variant mutations. METHODS. A consecutive series of

  16. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bernstein, Jonine L; Thomas, Duncan C; Shore, Roy E

    2013-01-01

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with ra...

  17. Prolyl carboxypeptidase mRNA expression in the mouse brain.

    Science.gov (United States)

    Jeong, Jin Kwon; Diano, Sabrina

    2014-01-13

    Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and α-MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic α-MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain. © 2013 Published by Elsevier B.V.

  18. BRCA1 DNA-binding activity is stimulated by BARD1.

    Science.gov (United States)

    Simons, Amanda M; Horwitz, Andrew A; Starita, Lea M; Griffin, Karen; Williams, R Scott; Glover, J N Mark; Parvin, Jeffrey D

    2006-02-15

    The breast- and ovarian-specific tumor suppressor BRCA1 has been implicated in numerous cellular processes, including transcription, ubiquitination, and DNA repair. Its tumor suppression activity is tightly linked to that of BARD1, a protein that heterodimerizes with BRCA1. It has been previously shown that BRCA1 binds to DNA, an interesting functional observation in light of the genetic data linking BRCA1 to DNA repair pathways. In this work, we reexamine the DNA-binding properties of BRCA1, comparing them with the DNA-binding properties of the BRCA1/BARD1 heterodimer. Because nuclear BRCA1 exists as a heterodimer with BARD1, it is likely that in vitro studies of the heterodimer will provide a more accurate model of physiologic conditions. Our results indicate that whereas BARD1 cannot directly bind DNA, it does enhance DNA binding by BRCA1. This is a surprising observation as both DNA-binding domains are distal to the BARD1-interacting RING domain of BRCA1. Further analysis of the dimerization reveals that the BRCA1/BARD1 interaction is not limited to the amino-terminal RING domains of each protein. The carboxyl terminus of BRCA1 contributes significantly to the stability of the heterodimer. We also show that the presence of BARD1 has a secondary effect, as autoubiquitination of BRCA1/BARD1 heterodimers additionally enhances the affinity of BRCA1 for DNA. Together, these data suggest that BRCA1 and BARD1 heterodimerization is stabilized via domains not previously thought to interact and that BARD1 acts in both ubiquitination-dependent and ubiquitination-independent ways to influence the role of BRCA1 in DNA repair.

  19. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

    Directory of Open Access Journals (Sweden)

    van de Vijver Marc J

    2010-11-01

    Full Text Available Abstract Background Basal-like breast cancers (BLBC are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from BRCA1-mutation carriers. The genomic instability of BRCA1-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose polymerase 1 (PARP1 inhibitors. Molecular similarities between BLBCs and BRCA1-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs. Methods There are several known molecular features characteristic for BRCA1-mutated breast tumors: 1 increased numbers of genomic aberrations, 2 a distinct pattern of genomic aberrations, 3 a high frequency of TP53 mutations and 4 a high incidence of complex, protein-truncating TP53 mutations. We compared the frequency of TP53 mutations and the pattern and amount of genomic aberrations between BRCA1-mutated breast tumors, BLBCs and luminal breast tumors by TP53 gene sequencing and array-based comparative genomics hybridization (aCGH analysis. Results We found that the high incidence of protein truncating TP53 mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors. Conclusions Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These

  20. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations.

    Science.gov (United States)

    Holstege, Henne; Horlings, Hugo M; Velds, Arno; Langerød, Anita; Børresen-Dale, Anne-Lise; van de Vijver, Marc J; Nederlof, Petra M; Jonkers, Jos

    2010-11-30

    Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from BRCA1-mutation carriers. The genomic instability of BRCA1-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and BRCA1-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs. There are several known molecular features characteristic for BRCA1-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of TP53 mutations and 4) a high incidence of complex, protein-truncating TP53 mutations. We compared the frequency of TP53 mutations and the pattern and amount of genomic aberrations between BRCA1-mutated breast tumors, BLBCs and luminal breast tumors by TP53 gene sequencing and array-based comparative genomics hybridization (aCGH) analysis. We found that the high incidence of protein truncating TP53 mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors. Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with

  1. Population testing for cancer predisposing BRCA1/BRCA2 mutations

    OpenAIRE

    Wardle, J.

    2014-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the...

  2. BRCA 1-Mediated Histone Monoubiquitylation: Effect on Nucleosome Dynamics

    Science.gov (United States)

    2008-02-01

    nucleosome positioning sequence from sea urchin 5s rRNA gene; perform and analyze the ubiquitylation reaction (month 4). Done Task 2: Use single... sea urchin 5S rDNA, and oligonucleosomes were reconstituted on the same sequence repeated in tandem (208-12) (Simpson et al., 1985). Isolation of...Center, Columbus, OH 43210), who provided BRCA1/BARD1 protein complex. b. Acquire and perform quality tests on the other components of the

  3. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair.

    Science.gov (United States)

    Starita, Lea M; Parvin, Jeffrey D

    2003-06-01

    Interest in BRCA1 stems from its role as a tumour suppressor in breast and ovarian cancer. Intensive research in BRCA1 has revealed little about its specific role in cancer; rather, this protein has been implicated in a multitude of important cellular processes. The diverse biochemical activities of BRCA1 combine to protect the genome from damage. New data reveal that BRCA1 transcriptionally regulates some DNA-repair genes, and, in addition, new roles for BRCA1 have been identified in heterochromatin formation on the X chromosome, double-strand-break repair, and ubiquitination. These diverse activities of BRCA1 may be linked in a single pathway, or BRCA1 might function in multiple nuclear processes.

  4. BRCA1 as a Therapeutic Target in Sporadic Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Katherine V. Clark-Knowles

    2010-01-01

    Full Text Available In sporadic epithelial ovarian cancer (EOC, the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients with BRCA1 germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.

  5. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ignacio Blanco

    Full Text Available While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR = 1.10, 95% confidence interval (CI 1.04-1.15, p = 1.9 x 10(-4 (false discovery rate (FDR-adjusted p = 0.043. Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045. Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05 for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  6. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    Science.gov (United States)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Ramón y Cajal, Teresa; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K; Toland, Amanda E; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Greene, Mark H; Mai, Phuong L; Nussbaum, Robert L; Andrulis, Irene L; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy R; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R; Hogervorst, Frans B L; van der Hout, Annemarie H; Seynaeve, Caroline; van der Luijt, Rob B; Ligtenberg, Marjolijn J L; Devilee, Peter; Wijnen, Juul T; Rookus, Matti A; Meijers-Heijboer, Hanne E J; Blok, Marinus J; van den Ouweland, Ans M W; Aalfs, Cora M; Rodriguez, Gustavo C; Phillips, Kelly-Anne A; Piedmonte, Marion; Nerenstone, Stacy R; Bae-Jump, Victoria L; O'Malley, David M; Ratner, Elena S; Schmutzler, Rita K; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M; Miron, Alex; Neuhausen, Susan L; Terry, Mary Beth; Chung, Wendy K; Daly, Mary B; Goldgar, David E; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elisabeth J; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K; Olah, Edith; Narod, Steven A; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N; Hamann, Ute; Spurdle, Amanda B; Healey, Sue; Weitzel, Jeffrey N; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M; Maxwell, Christopher A; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J; Antoniou, Antonis C; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  7. Women receiving news of a family BRCA1/2 mutation: messages of fear and empowerment.

    Science.gov (United States)

    Crotser, Cheryl B; Dickerson, Suzanne S

    2010-12-01

    Communication of genetic test results to healthy at-risk family members is complicated considering family dynamics and the complexity of cancer genetics. The purpose of this study was to understand the experience of family communication of BRCA1/2 results from the perspective of young and middle-aged women receiving the news. THEORETICAL RATIONALE: Individuals are self-interpretive beings influenced by family culture, history, and communication patterns. Humans express meaning through language and stories. Heideggerian hermeneutics guided in-depth interviews and team interpretation of data. Using purposive and network sampling, 19 women 18 to 50 years of age who received news of a family BRCA1/2 mutation from a biologic relative were recruited from support groups and two health facilities in upstate New York. Five themes emerged: (a) situating the story, (b) receiving the message from family, (c) responding to receipt of the message, (d) impacting family communication, and (e) advice for communicating risk. Two constitutive patterns were identified: (a) communicating risk as a message of fear and empowerment and (b) integrating the message by taking one step at a time. Healthcare professionals (HCPs) have an important role in provision of anticipatory guidance for communication of genetic test results, including the potential behavioral and emotional responses to family risk communication. Future research is indicated to understand the role of HCPs in family risk communication. Presentation of comprehensive and balanced information and the use of patient-centered communication is essential. HCPs need to view women as whole rather than as a person at risk. Continued support is needed for women who subsequently test positive or negative for the family BRCA1/2 mutation from HCPs and others, often outside the family network. © 2010 Sigma Theta Tau International.

  8. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

    NARCIS (Netherlands)

    Cox, D.G.; Simard, J.; Sinnett, D.; Hamdi, Y.; Soucy, P.; Ouimet, M.; Barjhoux, L.; Verny-Pierre, C.; McGuffog, L.; Healey, S.; Szabo, C.; Greene, M.H.; Mai, P.L.; Andrulis, I.L.; Thomassen, M.; Gerdes, A.M.; Caligo, M.A.; Friedman, E.; Laitman, Y.; Kaufman, B.; Paluch, S.S.; Borg, A.; Karlsson, P.; Askmalm, M.S.; Bustinza, G.B.; Nathanson, K.L.; Domchek, S.M.; Rebbeck, T.R.; Benitez, J.; Hamann, U.; Rookus, M.A.; Ouweland, A.M. van den; Ausems, M.G.; Aalfs, C.M.; Asperen, C.J. van; Devilee, P.; Gille, H.J.; Peock, S.; Frost, D.; Evans, D.G.; Eeles, R.; Izatt, L.; Adlard, J.; Paterson, J.; Eason, J.; Godwin, A.K.; Remon, M.A.; Moncoutier, V.; Gauthier-Villars, M.; Lasset, C.; Giraud, S.; Hardouin, A.; Berthet, P.; Sobol, H.; Eisinger, F.; Bressac de Paillerets, B.; Caron, O.; Delnatte, C.; Goldgar, D.; Miron, A.; Ozcelik, H.; Buys, S.; Southey, M.C.; Terry, M.B.; Singer, C.F.; Dressler, A.C.; Tea, M.K.; Hansen, T.V.; Johannsson, O.; Piedmonte, M.; Rodriguez, G.C.; Basil, J.B.; Blank, S.; Toland, A.E.; Montagna, M.; Isaacs, C.; Blanco, I.; Gayther, S.A.; Moysich, K.B.; Schmutzler, R.K.; Wappenschmidt, B.; Engel, C.; Meindl, A.; Ditsch, N.; Arnold, N.; Niederacher, D.; Sutter, C.; Gadzicki, D.; Fiebig, B.; Caldes, T.; Laframboise, R.; Nevanlinna, H.; Chen, X.; Beesley, J.; Spurdle, A.B.; Neuhausen, S.L.; Ding, Y.C.; Couch, F.J.; Wang, X.; Peterlongo, P.; Manoukian, S.; Bernard, L.; Radice, P.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; Stoppa-Lyonnet, D.; Mazoyer, S.; Sinilnikova, O.M.; Ligtenberg, M.J.L.; Hoogerbrugge, N.; et al.,

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly

  9. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Askmalm, Marie Stenmark; Bustinza, Gisela Barbany; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M. W.; Ausems, Margreet G. E. M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J. J. P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; tea, Muy-Kheng; Hansen, Thomas V. O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.; Glendon, Gord; Selander, Teresa; Weerasooriya, Nayana; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Liedgren, Sigrun; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Soller, Maria; Jernström, Helena; Harbst, Katja; Henriksson, Karin; Lindblom, Annika; Arver, Brita; von Wachenfeldt, Anna; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Brandell, Richard Rosenquist; Dahl, Niklas; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van't Veer, L. J.; van Leeuwen, F. E.; Rookus, M. A.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; Tilanus-Linthorst, M. M. A.; Seynaeve, C.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; van der Luijt, R. B.; van Os, T. A.; Gille, J. J. P.; Waisfisz, Q.; Meijers-Heijboer, H. E. J.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Cook, Margaret; Platte, Radka; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai-Ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Downing, Sarah; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Kennedy, M. John; Barton, David; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Davidson, Rosemarie; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Dorkins, Huw; Barwell, Julian; Chu, Carol; Miller, Julie; Ellis, Ian; Houghton, Catherine; Lalloo, Fiona; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Sinilnikova, Olga; Léone, Mélanie; Buecher, Bruno; Houdayer, Claude; Belotti, Muriel; Tirapo, Carole; de Pauw, Antoine; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Bonadona, Valérie; Bourdon, Violaine; Noguchi, Tetsuro; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Muller, Danièle; Fricker, Jean-Pierre; Longy, Michel; Sevenet, Nicolas; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hèléne; Rebischung, Christine; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Lebrun, Marine; Ferrer, Sandra Fert; Frénay, Marc; Vénat-Bouvet, Laurence; Mortemousque, Isabelle; Lynch, Henry T.; Snyder, Carrie L.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly

  10. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...

  11. Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment.

    Science.gov (United States)

    Seoane, Samuel; Arias, Efigenia; Sigueiro, Rita; Sendon-Lago, Juan; Martinez-Ordoñez, Anxo; Castelao, Esteban; Eiró, Noemí; Garcia-Caballero, Tomás; Macia, Manuel; Lopez-Lopez, Rafael; Maestro, Miguel; Vizoso, Francisco; Mouriño, Antonio; Perez-Fernandez, Roman

    2015-06-10

    The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown. We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels. Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy.

  12. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.

    Science.gov (United States)

    Holstege, Henne; Joosse, Simon A; van Oostrom, Conny Th M; Nederlof, Petra M; de Vries, Annemieke; Jonkers, Jos

    2009-04-15

    Approximately half of all hereditary breast cancers are compromised in their DNA repair mechanisms due to loss of BRCA1 or BRCA2 function. Previous research has found a strong correlation between BRCA mutation and TP53 mutation. However, TP53 mutation status is often indirectly assessed by immunohistochemical staining of accumulated p53 protein. We sequenced TP53 exons 2 to 9 in 21 BRCA1-related breast cancers and 37 sporadic breast tumors. Strikingly, all BRCA1-related breast tumors contained TP53 mutations, whereas only half of these tumors stained positive for p53 accumulation. Positive p53 staining correlates with the presence of TP53 hotspot mutations in both BRCA1-related and sporadic breast tumors. However, whereas the majority of sporadic breast tumors that stained negative for p53 accumulation had wild-type TP53, the majority of BRCA1-associated breast tumors that stained negative for p53 accumulation had protein-truncating TP53 mutations (nonsense, frameshift, and splice mutations). Therefore, the strong selection for p53 loss in BRCA1-related tumors is achieved by an increase of protein-truncating TP53 mutations rather than hotspot mutations. Hence, immunohistochemical detection of TP53 mutation could lead to misdiagnosis in approximately half of all BRCA1-related tumors. The presence of deleterious TP53 mutations in most, if not all, BRCA1-related breast cancers suggests that p53 loss of function is essential for BRCA1-associated tumorigenesis. BRCA1-related tumors may therefore be treated not only with drugs that target BRCA1 deficiency [e.g., poly(ADP-ribose) polymerase inhibitors] but also with drugs that selectively target p53-deficient cells. This raises interesting possibilities for combination therapies against BRCA1-deficient breast cancers and BRCA1-like tumors with homologous recombination deficiency.

  13. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

    NARCIS (Netherlands)

    Y. Hamdi (Yosr); Soucy, P. (Penny); Kuchenbaeker, K.B. (Karoline B.); Pastinen, T. (Tomi); A. Droit (Arnaud); Lemaçon, A. (Audrey); J.W. Adlard (Julian); K. Aittomäki (Kristiina); I.L. Andrulis (Irene); A. Arason (Adalgeir); N. Arnold (Norbert); B.K. Arun (Banu); J. Azzollini; A.L. Bane (Anita L.); Barjhoux, L. (Laure); D. Barrowdale (Daniel); J. Benítez (Javier); P. Berthet (Pascaline); M.J. Blok (Marinus); K.A. Bobolis (Kristie A.); V. Bonadona (Valérie); B. Bonnani (Bernardo); Bradbury, A.R. (Angela R.); C. Brewer (Carole); B. Buecher (Bruno); Buys, S.S. (Saundra S.); M.A. Caligo (Maria); Chiquette, J. (Jocelyne); W. Chung (Wendy); K.B.M. Claes (Kathleen B.M.); Daly, M.B. (Mary B.); F. Damiola (Francesca); R. Davidson (Rosemarie); M. de La Hoya (Miguel); K. De Leeneer (Kim); O. Díez (Orland); Y.C. Ding (Yuan); R. Dolcetti (Riccardo); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); D. Eccles (Diana); R. Eeles (Ros); Z. Einbeigi (Zakaria); B. Ejlertsen (Bent); EMBRACE; C.W. Engel (Christoph); Gareth Evans, D.; L. Feliubadaló (L.); L. Foretova (Lenka); F. Fostira (Florentia); Foulkes, W.D. (William D.); G. Fountzilas (George); E. Friedman (Eitan); D. Frost (Debra); P. Ganschow (Pamela); P.A. Ganz (Patricia A.); J. Garber (Judy); S.A. Gayther (Simon); GEMO Study Collaborators; A-M. Gerdes (Anne-Marie); G. Glendon (Gord); A.K. Godwin (Andrew K.); D. Goldgar (David); M.H. Greene (Mark H.); J. Gronwald (Jacek); E. Hahnen (Eric); U. Hamann (Ute); T.V.O. Hansen (Thomas); S. Hart (Stewart); J. Hays (John); HEBON; F.B.L. Hogervorst (Frans); P.J. Hulick (Peter); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); L. Izatt (Louise); A. Jakubowska (Anna); M. James (Margaret); R. Janavicius (Ramunas); U.B. Jensen; E.M. John (Esther); V. Joseph (Vijai); Just, W. (Walter); Kaczmarek, K. (Katarzyna); Karlan, B.Y. (Beth Y.); KConFab Investigators; C.M. Kets; J. Kirk (Judy); Kriege, M. (Mieke); Y. Laitman (Yael); Laurent, M. (Maïté); C. Lazaro (Conxi); Leslie, G. (Goska); K.J. Lester (Kathryn); F. Lesueur (Fabienne); A. Liljegren (Annelie); N. Loman (Niklas); J.T. Loud (Jennifer); S. Manoukian (Siranoush); Mariani, M. (Milena); S. Mazoyer (Sylvie); L. McGuffog (Lesley); E.J. Meijers-Heijboer (Hanne); A. Meindl (Alfons); A. Miller (Austin); M. Montagna (Marco); A.-M. Mulligan (Anna-Marie); K.L. Nathanson (Katherine); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); R.L. Nussbaum (Robert L.); Olah, E. (Edith); O.I. Olopade (Olufunmilayo I.); K.-R. Ong (Kai-Ren); J.C. Oosterwijk (Jan); A. Osorio (Ana); L. Papi (Laura); S.K. Park (Sue K.); Pedersen, I.S. (Inge Sokilde); B. Peissel (Bernard); P.P. Segura (Pedro Perez); P. Peterlongo (Paolo); C. Phelan (Catherine); P. Radice (Paolo); J. Rantala (Johanna); Rappaport-Fuerhauser, C. (Christine); G. Rennert (Gad); A.L. Richardson (Andrea); M. Robson (Mark); G.C. Rodriguez (Gustavo); M.A. Rookus (Matti); R.K. Schmutzler (Rita); N. Sevenet (Nicolas); Shah, P.D. (Payal D.); C.F. Singer (Christian); Slavin, T.P. (Thomas P.); Snape, K. (Katie); J. Sokolowska (Johanna); Sønderstrup, I.M.H. (Ida Marie Heeholm); M.C. Southey (Melissa); A.B. Spurdle (Amanda); Stadler, Z. (Zsofia); D. Stoppa-Lyonnet (Dominique); G. Sukiennicki (Grzegorz); C. Sutter (Christian); Tan, Y. (Yen); M.-K. Tea; P.J. Teixeira; A. Teulé (A.); S.-H. Teo; M.B. Terry (Mary Beth); M. Thomassen (Mads); L. Tihomirova (Laima); M. Tischkowitz (Marc); S. Tognazzo (Silvia); A.E. Toland (Amanda); N. Tung (Nadine); A.M.W. van den Ouweland (Ans); R.B. van der Luijt (Rob); K. van Engelen (Klaartje); E.J. van Rensburg (Elizabeth); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); J.T. Wijnen (Juul); R. Rebbeck (Timothy); G. Chenevix-Trench (Georgia); K. Offit (Kenneth); Couch, F.J. (Fergus J.); S. Nord (Silje); D.F. Easton (Douglas F.); A.C. Antoniou (Antonis C.); Simard, J. (Jacques)

    2016-01-01

    textabstractPurpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility

  14. Comparison of protein and mRNA expression evolution in humans and chimpanzees.

    Directory of Open Access Journals (Sweden)

    Ning Fu

    Full Text Available Even though mRNA expression levels are commonly used as a proxy for estimating functional differences that occur at the protein level, the relation between mRNA and protein expression is not well established. Further, no study to date has tested whether the evolutionary differences in mRNA expression observed between species reflect those observed in protein expression. Since a large proportion of mRNA expression differences observed between mammalian species appears to have no functional consequences for the phenotype, it is conceivable that many or most mRNA expression differences are not reflected at the protein level. If this is true, then differences in protein expression may largely reflect functional adaptations observed in species phenotypes. In this paper, we present the first direct comparison of mRNA and protein expression differences seen between humans and chimpanzees. We reproducibly find a significant positive correlation between mRNA expression and protein expression differences. This correlation is comparable in magnitude to that found between mRNA and protein expression changes at different developmental stages or in different physiological conditions within one species. Noticeably, this correlation is mainly due to genes with large expression differences between species. Our study opens the door to a new level of understanding of regulatory evolution and poses many new questions that remain to be answered.

  15. Vitamin D receptor, Retinoid X receptor and peroxisome proliferator-activated receptor γ are overexpressed in BRCA1 mutated breast cancer and predict prognosis.

    Science.gov (United States)

    Heublein, Sabine; Mayr, Doris; Meindl, Alfons; Kircher, Alexandra; Jeschke, Udo; Ditsch, Nina

    2017-04-20

    BRCA1 mutated breast cancers are commonly diagnosed as negative for classical hormone receptors i.e. estrogen receptor, progesterone receptor and/or Her2. Due to these common targets being absent the application of anti-endocrine therapies is rather limited and a certain focus has been set on discovering alternative target molecules. We recently highlighted thyroid hormone receptors (TRs) to predict prognosis in breast cancer patients that had been diagnosed a BRCA1 germline mutation. Vitamin D Receptor (VDR), Retinoid X Receptor (RXR) and Peroxisome Proliferator-activated Receptor γ (PPARγ) are known to interact with TRs by forming functional heterodimers. Whether VDR, RXR or PPARγ are expressed in BRCA1 mutated breast cancer or may even be present in case of triple negativity is not known. Hence the current study aimed to investigate VDR, RXR and PPARγ in BRCA1 mut breast cancer and to test whether any of the three may be associated with clinico-pathological criteria including overall survival. This study analyzed VDR, RXR and PPARγ by immunohistochemistry in BRCA1 associated (n = 38) and sporadic breast cancer (n = 79). Receptors were quantified by applying an established scoring system (IR-score) and were tested for association with clinico-pathological variables. VDR, RXR and PPARγ were detected in over 90% of triple negative BRCA1 mut breast cancer and were significantly (VDR: p < 0.001, RXR: p = 0.010, PPARγ: p < 0.001) overexpressed in BRCA1 mutated as compared to sporadic cancer cases. VDR and RXR positivity predicted prolonged overall survival only in BRCA1 mutated cases while such association was not observed in sporadic breast cancer. In conclusion, this is the first study to describe VDR, RXR and PPARγ in BRCA1 mutated breast cancer. Based on the data presented here these receptors may be hypothesized to potentially evolve as interesting markers or even targets in hereditary breast cancer. However, independent studies are

  16. BRCA1/2 associated cancer susceptibility: a clinical overview

    Directory of Open Access Journals (Sweden)

    Lypas Georgios

    2016-06-01

    Full Text Available The most frequently identified genetic cause of breast cancer is the germline mutation of BRCA1 and 2 genes. The carriers of these mutations are at high risk for breast and ovarian cancers and increased risk for pancreatic and prostate cancers. Personal and family history are routinely used to identify individuals at risk for carrying such mutations. Genetic counselling is required to guide them through genetic testing and risk management. Positive testing corresponds to a deleterious mutation, whereas negative testing is considered as uninformative; variants of unknown clinical significance are also classified as uninformative.

  17. Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.

    Science.gov (United States)

    Hirasawa, Akira; Masuda, Kenta; Akahane, Tomoko; Ueki, Arisa; Yokota, Megumi; Tsuruta, Tomohiko; Nomura, Hiroyuki; Kataoka, Fumio; Tominaga, Eiichiro; Banno, Kouji; Makita, Kazuya; Susumu, Nobuyuki; Sugano, Kokichi; Kosaki, Kenjiro; Kameyama, Kaori; Aoki, Daisuke

    2014-01-01

    This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

  18. BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer.

    Science.gov (United States)

    Shi, Tingyan; Wang, Pan; Xie, Caixia; Yin, Sheng; Shi, Di; Wei, Congchong; Tang, Wenbin; Jiang, Rong; Cheng, Xi; Wei, Qingyi; Wang, Qing; Zang, Rongyu

    2017-05-01

    BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP-ribose) polymerase (PARP). Despite a number of small-size hospital-based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next-generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population-related without an apparent founder origin. This hot-spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at-risk relatives. Mutation carriers may also benefit from PARP-targeted therapies. © 2017 UICC.

  19. Identification of BRCA1 Deficiency Using Multi-Analyte Estimation of BRCA1 and Its Repressors in FFPE Tumor Samples from Patients with Triple Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Aruna Korlimarla

    Full Text Available Apart from germ-line BRCA1-mutated breast cancers, a significant proportion of women with sporadic triple negative breast cancer (TNBC sub-type are known to harbour varying levels of BRCA1-dysfuction. There is currently no established diagnostic method to identify these patients.The analysis was performed on 183 primary breast cancer tumor specimens from our longitudinal case-series archived as formalin-fixed-paraffin-embedded (FFPE blocks comprising 71 TNBCs and 112 Hormone receptor positive HER2 negative (HR+HER2- tumors. Transcript levels of BRCA1 and two of its repressors ID4 and microRNA182 were determined by TaqMan quantitative PCR. BRCA1 protein was detected immunohistochemically with the MS110 antibody.The representation of BRCA1 and its repressor ID4 as a ratio led to improved separation of TNBCs from HR+HER2- compared to either measure by itself. We then dichotomised the continuous distribution of each of the three measurements (Protein, MIRNA and transcript:repressor ratio into categories of deficient (0 and adequate (1. A composite BRCA1 Deficiency Score (BDS was computed by the addition of the score for all three measures. Samples deficient on 2 or more measures were deemed to be BRCA1 deficient; and 40% of all TNBCs met this criterion.We propose here a simple multi-level assay of BRCA1 deficiency using the BRCA1:ID4 ratio as a critical parameter that can be performed on FFPE samples in clinical laboratories by the estimation of only 3 bio-markers. The ease of testing will hopefully encourage adoption and clinical validation.

  20. The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability.

    Science.gov (United States)

    Lüddecke, S; Ertych, N; Stenzinger, A; Weichert, W; Beissbarth, T; Dyczkowski, J; Gaedcke, J; Valerius, O; Braus, G H; Kschischo, M; Bastians, H

    2016-05-05

    BRCA1 is a tumor-suppressor gene associated with, but not restricted to, breast and ovarian cancer and implicated in various biological functions. During mitosis, BRCA1 and its positive regulator Chk2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability. However, the function of BRCA1 during mitosis has not been defined mechanistically. To gain insights into the mitotic role of BRCA1 in regulating microtubule assembly, we systematically identified proteins interacting with BRCA1 during mitosis and found the centrosomal protein Cep72 as a novel BRCA1-interacting protein. CEP72 is frequently upregulated in colorectal cancer tissues and overexpression of CEP72 mirrors the consequences of BRCA1 loss during mitosis. In detail, the overexpression of CEP72 causes an increase in microtubule plus end assembly, abnormal mitotic spindle formation and the induction of chromosomal instability. Moreover, we show that high levels of Cep72 counteract Chk2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly. Thus, CEP72 represents a putative oncogene in colorectal cancer that might negatively regulate the mitotic function of BRCA1 to ensure chromosomal stability.

  1. BRCA1 Interaction of Centrosomal Protein Nlp Is Required for Successful Mitotic Progression*♦

    Science.gov (United States)

    Jin, Shunqian; Gao, Hua; Mazzacurati, Lucia; Wang, Yang; Fan, Wenhong; Chen, Qiang; Yu, Wei; Wang, Mingrong; Zhu, Xueliang; Zhang, Chuanmao; Zhan, Qimin

    2009-01-01

    Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability. PMID:19509300

  2. Battle brewing over the BRCA1/2 gene patents.

    Science.gov (United States)

    Agovic, Amina

    2010-01-01

    The revolutionary discovery of the DNA and the successful mapping of the human genome have allowed scientists worldwide to engage in an unprecedented research on the cutting-edge biomedical technology such as the genetic engineering (gene-splicing or recombinant DNA). However, as is often the case with modern bio-technologies, genes related innovation is heavily dependent on strong patent protection primarily due to high costs of research and commercialisation in this area. The aim of this paper is to provide a description of the District Court Ruling in the case of Association for Molecular Pathology et al v United States Patent and Trademark Office et al (ACLU v Myriad). In doing so, the article provides information on the relevant background at issues, including a brief introduction to general patentability requirements in relation to genes and the controversy surrounding the patentability of genetic material. The analysis of the complaint filed in the ACLU v Myriad case and the details of the District Court Ruling follows. The paper concludes with an outlook of the future legal actions involving Myriad's BRCA1/2 and the assessment of the potential impact that the BRCA1/2 District Court Ruling and subsequent appeal(s) may have on the American patent law.

  3. Wwox-Brca1 interaction: role in DNA repair pathway choice.

    Science.gov (United States)

    Schrock, M S; Batar, B; Lee, J; Druck, T; Ferguson, B; Cho, J H; Akakpo, K; Hagrass, H; Heerema, N A; Xia, F; Parvin, J D; Aldaz, C M; Huebner, K

    2017-04-20

    In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1-Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers

  4. Wwox–Brca1 interaction: role in DNA repair pathway choice

    Science.gov (United States)

    Schrock, M S; Batar, B; Lee, J; Druck, T; Ferguson, B; Cho, J H; Akakpo, K; Hagrass, H; Heerema, N A; Xia, F; Parvin, J D; Aldaz, C M; Huebner, K

    2017-01-01

    In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1–Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers

  5. Responses of mRNA expression of PepT1 in small intestine to ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-05-04

    May 4, 2009 ... To study the effect of circulation small peptides concentration on mRNA expression in small intestine, graded amount of soybean small peptides (SSP) were infused into lactating goats through duodenal fistulas. Peptide-bound amino acid (PBAA) concentration in arterial plasma and the mRNA expression.

  6. Responses of mRNA expression of PepT1 in small intestine to ...

    African Journals Online (AJOL)

    To study the effect of circulation small peptides concentration on mRNA expression in small intestine, graded amount of soybean small peptides (SSP) were infused into lactating goats through duodenal fistulas. Peptide-bound amino acid (PBAA) concentration in arterial plasma and the mRNA expression of PepT1 was ...

  7. Expression of cVg1 mRNA during chicken embryonic development

    NARCIS (Netherlands)

    Somi, Semir; Houweling, Arjan C.; Buffing, Anita A. M.; Moorman, Antoon F. M.; van den Hoff, Maurice J. B.

    2003-01-01

    Using degenerated PCR-primers to identify known and novel BMPs that are expressed in the developing chicken heart, we identified not only BMP2, -4, and -7 mRNA, but also the TGFbeta superfamily member cVg1. The expression pattern of cVg1 mRNA was determined during chicken development from HH4 to

  8. Expression of mRNA of chemokine receptor CXCR4 in feline mammary adenocarcinoma.

    Science.gov (United States)

    Tanabe, S; Nakadai, T; Furuoka, H; Oomachi, T; Kobayashi, Y; Omata, Y; Koyama, T; Hondo, E; Uzuka, Y; Sarashina, T; Ducusin, R J T; Shida, T; Dorf, M E

    2002-12-14

    The expression of mRNA of the chemokine receptor CXCR4 in 65 surgically resected mammary adenocarcinomas from cats was investigated by in situ hybridisation. No expression of the receptor's mRNA was detectable in the mammary tissue of healthy cats, but it was expressed in areas adjacent to necrosis, surrounding blood vessels and cells infiltrating the lymphatics of 47 (72.3 per cent) of the 65 samples. There was a significant relationship between lymphatic infiltration by neoplastic cells and the expression of the receptor's mRNA (P < 0.005), but there was no significant relationship between its expression and the one-year survival of the cats.

  9. In their own words: treating very young BRCA1/2 mutation-positive women with care and caution.

    Directory of Open Access Journals (Sweden)

    Lindsey M Hoskins

    Full Text Available Young women who have been identified as carrying a deleterious mutation in BRCA1 or BRCA2 face a unique set of challenges related to managing cancer risk during a demographically-dense stage of life. They may struggle with decision-making in the absence of clear age-specific guidelines for medical management and because they have not yet fully developed the capacity to make life-altering decisions confidently. This study sought a patient-centered perspective on the dilemmas faced by 18-24 year olds who completed BRCA1/2 gene mutation testing prior to their 25(th birthdays.This study integrated qualitative data from three independent investigations of BRCA1/2-positive women recruited through cancer risk clinics, hospital-based research centers, and online organizations. All 32 participants were women aged 21-25 who tested positive for a BRCA1/2 gene mutation between 2 and 60 months prior to data collection. Investigators used techniques of grounded theory and interpretive description to conduct both within and cross-study analysis.Participants expressed needs for (1 greater clarity in recommendations for screening and prevention before age 25, especially with consideration of early and regular exposure to radiation associated with mammography or to hormones used in birth control, and (2 ongoing contact with providers to discuss risk management protocols as they become available.Health care needs during the young adult years evolve with the cognitive capacity to address abrupt and pressing change. Specific needs of women in this population include a desire to balance autonomous decision-making with supportive guidance, a need for clear, accurate and consistent medical recommendations. Optimally, these women are best cared for by a team of genetically-oriented providers as part of a sustained program of ongoing support, rather than seen in an episodic, crisis-driven fashion. A discussion of insurance issues and provider-patient cultural differences

  10. Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

    Science.gov (United States)

    Garcia, Amandine I; Buisson, Monique; Damiola, Francesca; Tessereau, Chloé; Barjhoux, Laure; Verny-Pierre, Carole; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Caron, Olivier; Gautier-Villars, Marion; Coupier, Isabelle; Buecher, Bruno; Vennin, Philippe; Belotti, Muriel; Lortholary, Alain; Gesta, Paul; Dugast, Catherine; Noguès, Catherine; Fricker, Jean-Pierre; Faivre, Laurence; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M; Mazoyer, Sylvie

    2016-01-01

    Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3′- untranslated regions (3′-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1- and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3′-UTR and one in BRCA2 3′-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3′-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3′-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity. PMID:26785832

  11. A cohort analysis of men with a family history of BRCA1/2 and Lynch mutations for prostate cancer.

    Science.gov (United States)

    Kerr, Lynne; Rewhorn, Matthew J; Longmuir, Mark; Fraser, Sioban; Walsh, Shaun; Andrew, Nicola; Leung, Hing Y

    2016-07-25

    Prostate cancer (PC) is a major health concern for men worldwide, with an estimated lifetime risk of ~14 %. A recent comprehensive analysis of mutational processes revealed ageing and mismatch repair as the only altered processes in PC. We wish to test if a cohort of men with inherited risk of mismatch repair defect through BRCA1/2 or Lynch Syndrome mutations represents a target population for prostate cancer testing. Fifty-eight men (aged 40-69 years) from families with a history of BRCA1/2 or HNPCC/Lynch mutations were invited to take part. Men with PSA >3.0 ng/ml were recommended to have transrectal ultrasound-guided prostatic biopsies. Overall 1 of 7 (14 %) and 1 of 20 (5 %) men with BRCA1/2 mutations were positive for a diagnosis of prostate cancer. In men with Lynch syndrome, 1 of 4 (25 %) was diagnosed to have prostate cancer. The index case with Lynch syndrome harbours a heterozygous mutation in the mismatch repair MSH6 gene. Near to complete loss of MSH6 immunoreactivity in the prostate tumour supports silencing of the remaining MSH6 allele during prostate carcinogenesis. The finding of near-to-complete loss of MSH6 expression in affected men with a family history of Lynch Syndrome supports its mechanistic involvement during prostate carcinogenesis. This work therefore contributes to the argument that, in certain male populations, Lynch Syndrome mutations are biologically implicated in men with prostate cancer.

  12. Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma

    Directory of Open Access Journals (Sweden)

    Sondes Karray-Chouayekh

    2009-01-01

    Full Text Available Aberrant hypermethylation of gene promoter regions is one of the mechanisms for inactivation of tumour suppressor genes in many human cancers including breast carcinoma. In the current study, we aimed to assess by MSP, the methylation pattern of two cancer-related genes involved in DNA repair: hMLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli and BRCA1 (breast cancer 1, early onset in 78 primary breast cancers from Tunisian patients. The methylation frequencies were 24.36% for hMLH1 and 46% for BRCA1. BRCA1 methylation correlated with age at diagnosis (P=.015 and 5-years disease free survival (P=.016 while hMLH1 methylation was more frequent in larger tumors (P=.002 and in presence of distant metastasis (P=.004. Furthermore, methylation of hMLH1 significantly correlated with high level of P53 expression (P=.006 and with overall survival (P=.015 suggesting that silencing of hMLH1 through aberrant promoter methylation could be used as a poor prognosis indicator in breast cancer.

  13. Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers

    Science.gov (United States)

    2013-01-01

    Introduction Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents. Methods We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers. Results Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell

  14. Applying the breaks on gene expression - mRNA deadenylation by Pop2p

    DEFF Research Database (Denmark)

    Andersen, Kasper Røjkjær; Jonstrup, Anette Thyssen; Van, Lan Bich

    When driving a car, control of the brakes is just as important as control of the accelerator pedal. Likewise, in gene expression, regulation of mRNA degradation is as important as regulation of its synthesis (Mühlemann, 2005). The rate-determining step of mRNA decay in eukaryotes seems to be the ......When driving a car, control of the brakes is just as important as control of the accelerator pedal. Likewise, in gene expression, regulation of mRNA degradation is as important as regulation of its synthesis (Mühlemann, 2005). The rate-determining step of mRNA decay in eukaryotes seems...

  15. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kosinova Veronika

    2008-05-01

    Full Text Available Abstract Background The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic during 1999–2006. Methods The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing. Results In 294 unrelated families (29.1% of the 1,010 probands pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2 represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G were demonstrated to result in aberrant transcripts and are considered as deleterious mutations. Conclusion This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.

  16. Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining

    NARCIS (Netherlands)

    J. Zhuang; J. Zhang (Shuzhong); H. Willers; H. Wang (Hong); J.H. Chung; D.C. van Gent (Dik); D.E. Hallahan; S.N. Powell; F. Xia

    2006-01-01

    textabstractThe tumor suppressor gene BRCA1 maintains genomic integrity by protecting cells from the deleterious effects of DNA double-strand breaks (DSBs). Through its interactions with the checkpoint kinase 2 (Chk2) kinase and Rad51, BRCA1 promotes homologous recombination, which

  17. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs aris...

  18. Modification of BRCA1 Breast Cancer Risk by Coffee Consumption: Potential Mechanisms for Biologic Effect

    National Research Council Canada - National Science Library

    Holt, Jeffrey

    2007-01-01

    The purpose of this study was to investigate the role of coffee and caffeine in the function of the DNA repair protein BRCA1 and to determine whether or not coffee and/or caffeine prevent BRCA1 hereditary breast cancer...

  19. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bancroft, Elizabeth K; Page, Elizabeth C; Castro, Elena

    2014-01-01

    AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng...

  20. Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients

    NARCIS (Netherlands)

    Papelard, H; de Bock, GH; van Eijk, R; Vlieland, TPMV; Cornelisse, CJ; Devilee, P; Tollenaar, RAEM

    The prevalence of disease-related BRCA1 mutations was investigated in 642 Dutch breast cancer patients not selected for family history or age at diagnosis. They were tested for germline mutations in the BRCA1 gene using an assay which detects small deletions and insertions (DSDI), as well as the two

  1. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation

    NARCIS (Netherlands)

    Meijers-Heijboer, H.; van Geel, B.; van Putten, W. L.; Henzen-Logmans, S. C.; Seynaeve, C.; Menke-Pluymers, M. B.; Bartels, C. C.; Verhoog, L. C.; van den Ouweland, A. M.; Niermeijer, M. F.; Brekelmans, C. T.; Klijn, J. G.

    2001-01-01

    Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women. We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were

  2. Identification of a founder BRCA1 mutation in the Moroccan population.

    Science.gov (United States)

    Quiles, F; Teulé, À; Martinussen Tandstad, N; Feliubadaló, L; Tornero, E; Del Valle, J; Menéndez, M; Salinas, M; Wethe Rognlien, V; Velasco, A; Izquierdo, A; Capellá, G; Brunet, J; Lázaro, C

    2016-10-01

    Breast cancer (BC) is the most frequent cancer among women in Morocco. However, the role of the most prevalent BC-predisposing genes, BRCA1 and BRCA2, has been largely unexplored. To help define the role of BRCA1 in BC in Morocco, we characterized the first potential BRCA1 founder mutation in this population. Genetic testing of BRCA1 and BRCA2 in BC high-risk families identified mutation BRCA1 c.5309G>T, p.(Gly1770Val) or G1770V in five independent families from Morocco, suggesting a founder effect. To confirm this hypothesis, haplotype construction was performed using seven intragenic and flanking BRCA1 microsatellite markers. Clinical data were also compiled. Clinical data from carriers of mutation G1770V correspond to data from carriers of BRCA1 pathogenic mutations. Microsatellite analysis showed a common haplotype for the five families in a region comprising 1.54 Mb, confirming G1770V as the first specific founder BRCA1 mutation in the Moroccan population. Our findings contribute to a better understanding of BC genetics in the Moroccan population. Nevertheless, comprehensive studies of mutation G1770V in large series of BC patients from Morocco are needed to assess the real prevalence of this mutation and to improve genetic testing and risk assessment in this population. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Male breast cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie

    2016-01-01

    BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs...

  4. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Unknown

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the major- ity of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian ...

  5. Analysis of BRCA1 involvement in breast cancer in Indian women

    Indian Academy of Sciences (India)

    The involvement of the familial breast-ovarian cancer gene (BRCA1) in the molecular pathogenesis of breast cancer among Indian women is unknown. We have used a set of microsatellite polymorphisms to examine the frequency of allele loss at the BRCA1 region on chromosome 17q21, in a panel of 80 human breast ...

  6. Identification and treatment of patients with BRCA1 or BRCA2-defective breast and ovarian cancer

    NARCIS (Netherlands)

    Schouten, P.C.

    2017-01-01

    Inactivating mutations in BRCA1 or BRCA2 confer a large lifetime risk of breast and ovarian cancer. These genes are involved in high-fidelity repair of DNA double strand breaks. Although defects in BRCA1 and BRCA2 are contributing to tumorigenesis, they may also form therapeutic targets. We

  7. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  8. Centrosomal microtubule nucleation activity is inhibited by BRCA1-dependent ubiquitination.

    Science.gov (United States)

    Sankaran, Satish; Starita, Lea M; Groen, Aaron C; Ko, Min Ji; Parvin, Jeffrey D

    2005-10-01

    In this study we find that the function of BRCA1 inhibits the microtubule nucleation function of centrosomes. In particular, cells in early S phase have quiescent centrosomes due to BRCA1 activity, which inhibits the association of gamma-tubulin with centrosomes. We find that modification of either of two specific lysine residues (Lys-48 and Lys-344) of gamma-tubulin, a known substrate for BRCA1-dependent ubiquitination activity, led to centrosome hyperactivity. Interestingly, mutation of gamma-tubulin lysine 344 had a minimal effect on centrosome number but a profound effect on microtubule nucleation function, indicating that the processes regulating centrosome duplication and microtubule nucleation are distinct. Using an in vitro aster formation assay, we found that BRCA1-dependent ubiquitination activity directly inhibits microtubule nucleation by centrosomes. Mutant BRCA1 protein that was inactive as a ubiquitin ligase did not inhibit aster formation by the centrosome. Further, a BRCA1 carboxy-terminal truncation mutant that was an active ubiquitin ligase lacked domains critical for the inhibition of centrosome function. These experiments reveal an important new functional assay regulated by the BRCA1-dependent ubiquitin ligase, and the results suggest that the loss of this BRCA1 activity could cause the centrosome hypertrophy and subsequent aneuploidy typically found in breast cancers.

  9. Characterization of RACK7 as a Novel Factor Involved in BRCA1 Mutation Mediated Breast Cancer

    Science.gov (United States)

    2012-10-01

    transcribed RNA polymerase II genes are impediments to replication fork progression in Saccharomyces cerevisiae . Mol Cell 34, 722-734 (2009). 18 11. Zou...isolated from adult mice containing one BRCA1 null allele and one floxed BRCA1 allele as described [36]. The cells were cultured in DMEM/F12 (1:1) medium

  10. Interleukin-21 mRNA expression during virus infections

    DEFF Research Database (Denmark)

    Holm, Christian; Nyvold, Charlotte Guldborg; Paludan, Søren Riis

    2006-01-01

    and activational effects of IL-21 on different leukocytes come into play in vivo in an immune response has so far not been fully investigated. We show here for the first time in vivo, that IL-21 mRNA is produced in the spleen when mice are challenged with herpes simplex virus type 2 (HSV-2) or lymphocytic...... choriomeningitis virus (LCMV). We show in HSV-2 challenged mice that this production takes place in CD4+ T cell fractions and is absent in CD4+ T cell-depleted fractions. We also show that the peak of IL-21 mRNA production in both the HSV-2 and LCMV-challenged mice coincides with the onset of the adaptive immune...... response. Thus, our data suggest a role for IL-21 in the early stages of adaptive immune response against virus infections....

  11. Refined histopathological predictors of BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T

    2014-01-01

    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess...... pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation...... status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation...

  12. Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark

    DEFF Research Database (Denmark)

    Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe

    2006-01-01

    Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations......, but BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested...... negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which...

  13. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara

    2014-01-01

    This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy...... at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from...... DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2...

  14. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine

    2009-01-01

    BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated...... in a small number of studies. METHODS: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox...... proportional hazards framework. RESULTS: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had...

  15. Levels of DNA Methylation Vary at CpG Sites across the BRCA1 Promoter, and Differ According to Triple Negative and "BRCA-Like" Status, in Both Blood and Tumour DNA.

    Directory of Open Access Journals (Sweden)

    Sarah L Daniels

    Full Text Available Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007. The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively. Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively. This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies.

  16. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

    Science.gov (United States)

    Nolan, Emma; Vaillant, François; Branstetter, Daniel; Pal, Bhupinder; Giner, Göknur; Whitehead, Lachlan; Lok, Sheau W; Mann, Gregory B; Rohrbach, Kathy; Huang, Li-Ya; Soriano, Rosalia; Smyth, Gordon K; Dougall, William C; Visvader, Jane E; Lindeman, Geoffrey J

    2016-08-01

    Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.

  17. Genetic heterogeneity in hereditary breast cancer: Role of BRCA1 and BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Rebbeck, T.R.; Couch, F.J.; Kant, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)

    1996-09-01

    The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer. 19 refs., 1 fig., 3 tabs.

  18. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements.

    Science.gov (United States)

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014).

  19. Dietary glycerol for quail: association between productive performance and COX III mRNA expression.

    Science.gov (United States)

    Silva, S C C; Gasparino, E; Batista, E; Tanamati, F; Vesco, A P D; Lala, B; de Oliveira, D P

    2016-05-25

    This study was carry out to evaluate mRNA expression of mitochondrial cytochrome c oxidase III in the Pectoralis superficialis muscle of 28-day-old quails fed diets containing 0, 8, and 12% glycerol. Total RNA was extracted (N = 10) and cDNA was amplified using specifics primers for qRT-PCR. Feed efficiency and feed intake were evaluated. COX III mRNA expression in breast muscle was higher in the group fed with 12% glycerol (0.863 AU); no differences were observed in the expression of this gene between the muscle of animals fed diets without glycerol (0.357 AU) and 8% glycerol (0.415 AU). Quails that showed greater COX III mRNA expression also showed the lowest feed efficiency. These results show that there is a difference in COX III mRNA expression in breast muscle of 28-day-old quail fed diets different concentrations of glycerol.

  20. Nonparametric testing for DNA copy number induced differential mRNA gene expression

    NARCIS (Netherlands)

    van Wieringen, W.N.; van de Wiel, M.A.

    2009-01-01

    The central dogma of molecular biology relates DNA with mRNA. Array CGH measures DNA copy number and gene expression microarrays measure the amount of mRNA. Methods that integrate data from these two platforms may uncover meaningful biological relationships that further our understanding of cancer.

  1. Quantification of substance P mRNA expression in the midbrain of ...

    African Journals Online (AJOL)

    This study was designed to develop a SYBR green I-based real-time polymerase chain reaction (RTPCR) for quantitative detection of substance P (SP) mRNA in the midbrain of ovariectomized migraine rats and to evaluate the effects of estradiol on the mRNA expression of SP in order to shed light on the mechanisms ...

  2. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Marquart, Louise; McGuffog, Lesley

    2011-01-01

    Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies.......Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies....

  3. Prefrontal cortical–striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity

    Science.gov (United States)

    Simon, Nicholas W.; Beas, Blanca S.; Montgomery, Karienn S.; Haberman, Rebecca P.; Bizon, Jennifer L.; Setlow, Barry

    2014-01-01

    Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making. PMID:23510331

  4. Elevated proto-oncogene and collagen mRNA expression in PVR retinas.

    Science.gov (United States)

    Hollborn, Margrit; Faude, Frank; Wiedemann, Peter; Kohen, Leon

    2003-05-01

    Retinal detachment is often accompanied by proliferation and migration of retinal cells and by increased synthesis of structural proteins, known as proliferative vitreoretinopathy (PVR). Herein we investigate the messenger RNA (mRNA) expression of proto-oncogenes responsible for cell proliferation and of structural proteins that have a role in membrane formation. Retinal samples were obtained from patients undergoing vitreoretinal surgery for the treatment of retinal detachment complicated by PVR. Normal human control retinas were obtained from cornea donors. The mRNA expression of the proto-oncogenes c- myc, c- fos and the proliferation marker Ki67, as well as of collagen type III and type IV, were investigated using the ribonuclease protection assay. Ki67 mRNA expression was not detectable in either sample type, but c- fos and c- myc mRNA expression was found in normal and PVR retinas. Whereas the expression of c- myc showed a marginal increase, the up-regulation in c- fos expression was strongly significant (5.07-fold). The mRNA of collagen type III was detectable at widely varying levels in all the PVR retinas but was found in only 2 of the 16 analysed normal samples. Collagen type IV mRNA was expressed in both PVR and control samples but was higher (2.21-fold) in the PVR retinas. These results indicate that an up-regulation of the proto-oncogene c- fos occurs in human PVR retinas. An increase in mRNA expression of collagen types III and IV takes place simultaneously. These changes in mRNA expression appear to be mainly connected to the initiation of cell proliferation, dedifferentiation and formation of tractional membranes.

  5. Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2

    Energy Technology Data Exchange (ETDEWEB)

    Coleman, C.N. [Harvard Medical School (United States). Joint Center for Radiation Therapy

    1999-07-01

    The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies.

  6. Astrocyte cultures derived from human brain tissue express angiotensinogen mRNA

    Energy Technology Data Exchange (ETDEWEB)

    Milsted, A.; Barna, B.P.; Ransohoff, R.M.; Brosnihan, K.B.; Ferrario, C.M. (Cleveland Clinic Foundation, OH (USA))

    1990-08-01

    The authors have identified human cultured cell lines that are useful for studying angiotensinogen gene expression and its regulation in the central nervous system. A model cell system of human central nervous system origin expressing angiotensinogen has not previously been available. Expression of angiotensinogen mRNA appears to be a basal property of noninduced human astrocytes, since astrocytic cell lines derived from human glioblastomas or nonneoplastic human brain tissue invariably produced angiotensinogen mRNA. In situ hybridization histochemistry revealed that angiotensinogen mRNA production was not limited to a subpopulation of astrocytes because >99% of cells in these cultures contained angiotensinogen mRNA. These cell lines will be useful in studies of the molecular mechanisms controlling angiotensin synthesis and the role of biologically active angiotensin in the human brain by allowing the authors to examine regulation of expression of the renin-angiotensin system in human astrocyte cultures.

  7. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei

    2015-01-01

    IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained...

  8. Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study.

    NARCIS (Netherlands)

    Chang-Claude, J.; Andrieu, N.; Rookus, M.A.; Brohet, R.M.; Antoniou, A.C.; Peock, S.; Davidson, R.; Izatt, L.; Cole, T.; Nogues, C.; Luporsi, E.; Huiart, L.; Hoogerbrugge, N.; Leeuwen, F.E. van; Osorio, A.; Eyfjord, J.; Radice, P.; Goldgar, D.E.; Easton, D.F.

    2007-01-01

    BACKGROUND: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. METHODS: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2

  9. BRCA1-like signature in triple negative breast cancer : Molecular and clinical characterization reveals subgroups with therapeutic potential

    NARCIS (Netherlands)

    Severson, Tesa M; Peeters, Justine; Majewski, Ian; Michaut, Magali; Bosma, Astrid; Schouten, Philip C; Chin, Suet-Feung; Pereira, Bernard; Goldgraben, Mae A; Bismeijer, Tycho; Kluin, Roelof J C; Muris, Jettie J F; Jirström, Karin; Kerkhoven, Ron M; Wessels, Lodewyk; Caldas, Carlos; Bernards, René; Simon, Iris M; Linn, S.C.

    2015-01-01

    Triple negative (TN) breast cancers make up some 15% of all breast cancers. Approximately 10-15% are mutant for the tumor suppressor, BRCA1. BRCA1 is required for homologous recombination-mediated DNA repair and deficiency results in genomic instability. BRCA1-mutated tumors have a specific pattern

  10. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Whiley, Phillip J; Thompson, Bryony

    2012-01-01

    Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional...

  11. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

    DEFF Research Database (Denmark)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B

    2017-01-01

    for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects...

  12. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

    NARCIS (Netherlands)

    Rebbeck, Timothy R.; Mitra, Nandita; Wan, Fei; Sinilnikova, Olga M.; Healey, Sue; McGuffog, Lesley; Mazoyer, Sylvie; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.; Nathanson, Katherine L.; Laitman, Yael; Kushnir, Anya; Paluch-Shimon, Shani; Berger, Raanan; Zidan, Jamal; Friedman, Eitan; Ehrencrona, Hans; Stenmark-Askmalm, Marie; Einbeigi, Zakaria; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Melin, Beatrice; Huo, Dezheng; Olopade, Olufunmilayo I.; Seldon, Joyce; Ganz, Patricia A.; Nussbaum, Robert L.; Chan, Salina B.; Odunsi, Kunle; Gayther, Simon A.; Domchek, Susan M.; Arun, Banu K.; Lu, Karen H.; Mitchell, Gillian; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Godwin, Andrew K.; Pathak, Harsh; Ross, Eric; Daly, Mary B.; Whittemore, Alice S.; John, Esther M.; Miron, Alexander; Terry, Mary Beth; Chung, Wendy K.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; Neuhausen, Susan L.; Ding, Yuan Chun; Ejlertsen, Bent; Gerdes, Anne-Marie; Hansen, Thomas v O.; Ramón Y Cajal, Teresa; Osorio, Ana; Benitez, Javier; Godino, Javier; Tejada, Maria-Isabel; Duran, Mercedes; Weitzel, Jeffrey N.; Bobolis, Kristie A.; Sand, Sharon R.; Fontaine, Annette; Savarese, Antonella; Pasini, Barbara; Peissel, Bernard; Bonanni, Bernardo; Zaffaroni, Daniela; Vignolo-Lutati, Francesca; Scuvera, Giulietta; Giannini, Giuseppe; Bernard, Loris; Genuardi, Maurizio; Radice, Paolo; Dolcetti, Riccardo; Manoukian, Siranoush; Pensotti, Valeria; Gismondi, Viviana; Yannoukakos, Drakoulis; Fostira, Florentia; Garber, Judy; Torres, Diana; Rashid, Muhammad Usman; Hamann, Ute; Peock, Susan; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Rosalind; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Izatt, Louise; Adlard, Julian; Donaldson, Alan; Ellis, Steve; Sharma, Priyanka; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Becker, Alexandra; Rhiem, Kerstin; Hahnen, Eric; Engel, Christoph; Meindl, Alfons; Engert, Stefanie; Ditsch, Nina; Arnold, Norbert; Plendl, Hans Jörg; Mundhenke, Christoph; Niederacher, Dieter; Fleisch, Markus; Sutter, Christian; Bartram, C. R.; Dikow, Nicola; Wang-Gohrke, Shan; Gadzicki, Dorothea; Steinemann, Doris; Kast, Karin; Beer, Marit; Varon-Mateeva, Raymonda; Gehrig, Andrea; Weber, Bernhard H.; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Belotti, Muriel; Gauthier-Villars, Marion; Damiola, Francesca; Boutry-Kryza, Nadia; Lasset, Christine; Sobol, Hagay; Peyrat, Jean-Philippe; Muller, Danièle; Fricker, Jean-Pierre; Collonge-Rame, Marie-Agnès; Mortemousque, Isabelle; Nogues, Catherine; Rouleau, Etienne; Isaacs, Claudine; de Paepe, Anne; Poppe, Bruce; Claes, Kathleen; de Leeneer, Kim; Piedmonte, Marion; Rodriguez, Gustavo; Wakely, Katie; Boggess, John; Blank, Stephanie V.; Basil, Jack; Azodi, Masoud; Phillips, Kelly-Anne; Caldes, Trinidad; de la Hoya, Miguel; Romero, Atocha; Nevanlinna, Heli; Aittomäki, Kristiina; van der Hout, Annemarie H.; Hogervorst, Frans B. L.; Verhoef, Senno; Collée, J. Margriet; Seynaeve, Caroline; Oosterwijk, Jan C.; Gille, Johannes J. P.; Wijnen, Juul T.; Gómez Garcia, Encarna B.; Kets, Carolien M.; Ausems, Margreet G. E. M.; Aalfs, Cora M.; Devilee, Peter; Mensenkamp, Arjen R.; Kwong, Ava; Olah, Edith; Papp, Janos; Diez, Orland; Lazaro, Conxi; Darder, Esther; Blanco, Ignacio; Salinas, Mónica; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Złowocka-Perłowska, Elżbieta; Menkiszak, Janusz; Arason, Adalgeir; Barkardottir, Rosa B.; Simard, Jacques; Laframboise, Rachel; Montagna, Marco; Agata, Simona; Alducci, Elisa; Peixoto, Ana; Teixeira, Manuel R.; Spurdle, Amanda B.; Lee, Min Hyuk; Park, Sue K.; Kim, Sung-Won; Friebel, Tara M.; Couch, Fergus J.; Lindor, Noralane M.; Pankratz, Vernon S.; Guidugli, Lucia; Wang, Xianshu; Tischkowitz, Marc; Foretova, Lenka; Vijai, Joseph; Offit, Kenneth; Robson, Mark; Rau-Murthy, Rohini; Kauff, Noah; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; tea, Muy-Kheng; Berger, Andreas; Greene, Mark H.; Mai, Phuong L.; Imyanitov, Evgeny N.; Toland, Amanda Ewart; Senter, Leigha; Bojesen, Anders; Pedersen, Inge Sokilde; Skytte, Anne-Bine; Sunde, Lone; Thomassen, Mads; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Caligo, Maria Adelaide; Aretini, Paolo; teo, Soo-Hwang; Selkirk, Christina G.; Hulick, Peter J.; Andrulis, Irene

    2015-01-01

    IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained

  13. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    NARCIS (Netherlands)

    R. Rebbeck (Timothy); N. Mitra (Nandita); F. Wan (Fei); O. Sinilnikova (Olga); S. Healey (Sue); L. McGuffog (Lesley); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); K.L. Nathanson (Katherine); Y. Laitman (Yael); A. Kushnir (Anya); S. Paluch-Shimon (Shani); R. Berger (Raanan); J. Zidan (Jamal); E. Friedman (Eitan); H. Ehrencrona (Hans); M. Stenmark-Askmalm (Marie); Z. Einbeigi (Zakaria); N. Loman (Niklas); K. Harbst (Katja); J. Rantala (Johanna); B. Melin (Beatrice); D. Huo (Dezheng); O.I. Olopade (Olofunmilayo); J.L. Seldon (Joyce); P.A. Ganz (Patricia); R.L. Nussbaum (Robert L.); S. Chan (Salina); K. Odunsi (Kunle); S.A. Gayther (Simon); S.M. Domchek (Susan); B.K. Arun (Banu); K.H. Lu (Karen); G. Mitchell (Gillian); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); A.K. Godwin (Andrew); S.S. Pathak; E.B. Ross (Eric); M.J. Daly (Mark); A.S. Whittemore (Alice); E.M. John (Esther); A. Miron (Alexander); M.B. Terry (Mary Beth); W.K. Chung (Wendy K.); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); T.V.O. Hansen (Thomas); T. Ramon Y Cajal; A. Osorio (Ana); J. Benítez (Javier); J. Godino (Javier); M.I. Tejada; M. Duran (Mercedes); J.N. Weitzel (Jeffrey); K.A. Bobolis (Kristie A.); S.R. Sand (Sharon); A. Fontaine (Annette); A. Savarese (Antonella); B. Pasini (Barbara); B. Peissel (Bernard); B. Bonnani (Bernardo); D. Zaffaroni (Daniela); F. Vignolo-Lutati (Francesca); G. Scuvera (Giulietta); G. Giannini (Giuseppe); L. Bernard (Loris); M. Genuardi (Maurizio); P. Radice (Paolo); R. Dolcetti (Riccardo); S. Manoukian (Siranoush); V. Pensotti (Valeria); V. Gismondi (Viviana); D. Yannoukakos (Drakoulis); F. Fostira (Florentia); J. Garber (Judy); D. Torres (Diana); M.U. Rashid (Muhammad); U. Hamann (Ute); S. Peock (Susan); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); R. Eeles (Rosalind); R. Davidson (Rosemarie); D. Eccles (Diana); T. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); S. Hodgson (Shirley); P.J. Morrison (Patrick); L.J. Walker (Lisa); M.E. Porteous (Mary); M.J. Kennedy (John); L. Izatt (Louise); L. Adlard; A. Donaldson (Alan); S.D. Ellis (Steve); P. Sharma (Priyanka); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Becker (Alexandra); K. Rhiem (Kerstin); E. Hahnen (Eric); C.W. Engel (Christoph); A. Meindl (Alfons); S. Engert (Stefanie); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); C. Mundhenke (Christoph); D. Niederacher (Dieter); M.C. Fleisch (Markus); C. Sutter (Christian); C.R. Bartram; N. Dikow (Nicola); S. Wang-Gohrke (Shan); D. Gadzicki (Dorothea); D. Steinemann (Doris); K. Kast (Karin); M. Beer (Marit); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); B.H.F. Weber (Bernhard); D. Stoppa-Lyonnet (Dominique); M. Belotti (Muriel); M. Gauthier-Villars (Marion); F. Damiola (Francesca); N. Boutry-Kryza (N.); C. Lasset (Christine); H. Sobol (Hagay); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); M.-A. Collonge-Rame; I. Mortemousque (Isabelle); C. Nogues (Catherine); E. Rouleau (Etienne); C. Isaacs (Claudine); A. de Paepe (Anne); B. Poppe (Bruce); K. Claes (Kathleen); K. De Leeneer (Kim); M. Piedmonte (Marion); G. Rodriguez (Gustavo); K. Wakely (Katie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); K.-A. Phillips (Kelly-Anne); T. Caldes (Trinidad); M. de La Hoya (Miguel); A. Romero (Atocha); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A.H. van der Hout (Annemarie); F.B.L. Hogervorst (Frans); S. Verhoef; J.M. Collee (Margriet); C.M. Seynaeve (Caroline); J.C. Oosterwijk (Jan); J.J. Gille (Johan); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); C.M. Kets; M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); P. Devilee (Peter); A.R. Mensenkamp (Arjen); A. Kwong (Ava); E. Olah; J. Papp (Janos); O. Díez (Orland); C. Lazaro (Conxi); E. Darder (Esther); I. Blanco (Ignacio); M. Salinas; A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); G. Sukiennicki (Grzegorz); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); A. Toloczko-Grabarek (Aleksandra); E. Złowocka-Perłowska (Elzbieta); J. Menkiszak (Janusz); A. Arason (Adalgeir); R.B. Barkardottir (Rosa); J. Simard (Jacques); R. Laframboise (Rachel); M. Montagna (Marco); S. Agata (Simona); E. Alducci (Elisa); A. Peixoto (Ana); P.J. Teixeira; A.B. Spurdle (Amanda); M.H. Lee (Min Hyuk); S.K. Park (Sue); S.-W. Kim (Sung-Won); M.O.W. Friebel (Mark ); F.J. Couch (Fergus); N.M. Lindor (Noralane); V.S. Pankratz (Shane); L. Guidugli (Lucia); X. Wang (Xianshu); M. Tischkowitz (Marc); L. Foretova (Lenka); J. Vijai (Joseph); K. Offit (Kenneth); M. Robson (Mark); R. Rau-Murthy (Rohini); N. Kauff (Noah); A. Fink-Retter (Anneliese); C.F. Singer (Christian); C. Rappaport (Christine); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); M.-K. Tea; A. Berger (Andreas); M.H. Greene (Mark); P.L. Mai (Phuong); E.N. Imyanitov (Evgeny); A.E. Toland (Amanda); L. Senter (Leigha); A. Bojesen (Anders); I.S. Pedersen (Inge Sokilde); A.-B. Skytte (Anne-Bine); L. Sunde (Lone); M. Thomassen (Mads); S.T. Moeller (Sanne Traasdahl); T.A. Kruse (Torben); U.B. Jensen; M.A. Caligo (Maria); P. Aretini (Paolo); S.-H. Teo; C.G. Selkirk (Christina); P.J. Hulick (Peter); I.L. Andrulis (Irene)

    2015-01-01

    textabstractImportance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere

  14. BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven.

    Science.gov (United States)

    Wiltshire, Timothy; Senft, Jamie; Wang, Yutian; Konat, Gregory W; Wenger, Sharon L; Reed, Eddie; Wang, Weixin

    2007-04-01

    Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anticancer agents that are analogs of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. We demonstrated previously that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and that BRCA1 may affect chemosensitivity by controlling cell cycle checkpoints, DNA repair, and genomic stability in response to irofulven treatment. We observed that irofulven induces the formation of chromosome breaks and radials and the activation and foci formation of gamma-H2AX, BRCA1, and RAD51. We also provided evidence that irofulven induces the generation of DNA double-strand breaks. By using BRCA1-deficient or -proficient cells, we demonstrated that in response to irofulven, BRCA1 contributes to the control of S and G(2)/M cell cycle arrest and is critical for repairing DNA double-strand breaks and for RAD51-dependent homologous recombination. Furthermore, we found that BRCA1 deficiency results in increased chromosome damage and chemosensitivity after irofulven treatment.

  15. Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function.

    Science.gov (United States)

    Sankaran, Satish; Starita, Lea M; Simons, Amanda M; Parvin, Jeffrey D

    2006-04-15

    The breast and ovarian cancer specific tumor suppressor BRCA1, bound to BARD1, has multiple functions aimed at maintaining genomic stability in the cell. We have shown earlier that the BRCA1/BARD1 E3 ubiquitin ligase activity regulates centrosome-dependent microtubule nucleation. In this study, we tested which domains of BRCA1 and BARD1 were required to control the centrosome function. In the present study, (a) we confirmed that the ubiquitination activity of BRCA1 regulates centrosome number and function in Hs578T breast cancer cells; (b) we observed that both the amino and carboxyl termini of BRCA1 are required for regulation of centrosome function in vitro; (c) an internal domain (770-1,290) is dispensable for centrosome regulation; (d) BARD1 is required for regulation of centrosome function and protein sequences within the terminal 485 amino acids are necessary for activity; and (e) BARD1 is localized at the centrosome throughout the cell cycle. We conclude that the BRCA1-dependent E3 ubiquitin ligase functions to restrain centrosomes in mammary cells, and loss of BRCA1 in the precancerous breast cell leads to centrosomal hypertrophy, a phenotype commonly observed in incipient breast cancer.

  16. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    Directory of Open Access Journals (Sweden)

    Wang Jufang

    2011-08-01

    Full Text Available Abstract Background Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Methods Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Results Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. Conclusions The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

  17. CD133 mRNA expression and microsatellite instability in colorectal carcinoma.

    Science.gov (United States)

    Huh, Jung Wook; Park, Yeon Sun; Lee, Jae Hyuk; Kim, Hyeong Rok; Shin, Myung Geun; Kim, Young Jin

    2010-12-01

    The present study was performed to examine the CD133 expression in colorectal cancer and to analyze its relationship with microsatellite instability (MSI) and the clinicopathological factors, including patient survival. The CD133 mRNA levels in 61 primary colorectal adenocarcinomas were analyzed by reverse transcriptase-polymerase chain reaction, with normalization relative to GAPDH. Five microsatellite markers were analyzed to evaluate MSI. A CD133 mRNA expression was significantly associated with the depth of invasion (P = 0.017), lymph node involvement (P = 0.012), and lymphovascular invasion (P = 0.019). A CD133 expression was significantly correlated with the MSI status (P = 0.035). With a median follow-up period of 45 months, the 5-year disease-free survival rate of patients with a low CD133 mRNA expression was significantly higher than that of those patients with high levels of CD133 mRNA expression (82.9% and 59.0%, respectively; P = 0.027). However, on the multivariate analysis, a CD133 mRNA expression was not an independent predictor of disease-free survival. Elevated CD133 mRNA levels may represent more aggressive tumor biology and poorer survival in patients with colorectal cancer, correlating with a high level of MSI status. Larger prospective studies are required to confirm these findings. © 2010 Wiley-Liss, Inc.

  18. Carboxylesterase 1 gene duplication and mRNA expression in adipose tissue are linked to obesity and metabolic function

    DEFF Research Database (Denmark)

    Friedrichsen, Martin; Poulsen, Pernille; Wojtaszewski, Jørgen

    2013-01-01

    involved in the control of mRNA expression. Here, we investigated mRNA expression level in adipose tissue and its association with measures of adiposity and metabolic function in a population of elderly twins. Furthermore, the heritability of mRNA expression level in adipose tissue and the effect of gene...

  19. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

    Science.gov (United States)

    Silvestri, Valentina; Barrowdale, Daniel; Mulligan, Anna Marie; Neuhausen, Susan L; Fox, Stephen; Karlan, Beth Y; Mitchell, Gillian; James, Paul; Thull, Darcy L; Zorn, Kristin K; Carter, Natalie J; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Ramus, Susan J; Nussbaum, Robert L; Olopade, Olufunmilayo I; Rantala, Johanna; Yoon, Sook-Yee; Caligo, Maria A; Spugnesi, Laura; Bojesen, Anders; Pedersen, Inge Sokilde; Thomassen, Mads; Jensen, Uffe Birk; Toland, Amanda Ewart; Senter, Leigha; Andrulis, Irene L; Glendon, Gord; Hulick, Peter J; Imyanitov, Evgeny N; Greene, Mark H; Mai, Phuong L; Singer, Christian F; Rappaport-Fuerhauser, Christine; Kramer, Gero; Vijai, Joseph; Offit, Kenneth; Robson, Mark; Lincoln, Anne; Jacobs, Lauren; Machackova, Eva; Foretova, Lenka; Navratilova, Marie; Vasickova, Petra; Couch, Fergus J; Hallberg, Emily; Ruddy, Kathryn J; Sharma, Priyanka; Kim, Sung-Won; Teixeira, Manuel R; Pinto, Pedro; Montagna, Marco; Matricardi, Laura; Arason, Adalgeir; Johannsson, Oskar Th; Barkardottir, Rosa B; Jakubowska, Anna; Lubinski, Jan; Izquierdo, Angel; Pujana, Miguel Angel; Balmaña, Judith; Diez, Orland; Ivady, Gabriella; Papp, Janos; Olah, Edith; Kwong, Ava; Nevanlinna, Heli; Aittomäki, Kristiina; Perez Segura, Pedro; Caldes, Trinidad; Van Maerken, Tom; Poppe, Bruce; Claes, Kathleen B M; Isaacs, Claudine; Elan, Camille; Lasset, Christine; Stoppa-Lyonnet, Dominique; Barjhoux, Laure; Belotti, Muriel; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Engel, Christoph; Niederacher, Dieter; Steinemann, Doris; Hahnen, Eric; Kast, Karin; Arnold, Norbert; Varon-Mateeva, Raymonda; Wand, Dorothea; Godwin, Andrew K; Evans, D Gareth; Frost, Debra; Perkins, Jo; Adlard, Julian; Izatt, Louise; Platte, Radka; Eeles, Ros; Ellis, Steve; Hamann, Ute; Garber, Judy; Fostira, Florentia; Fountzilas, George; Pasini, Barbara; Giannini, Giuseppe; Rizzolo, Piera; Russo, Antonio; Cortesi, Laura; Papi, Laura; Varesco, Liliana; Palli, Domenico; Zanna, Ines; Savarese, Antonella; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Bonanni, Bernardo; Viel, Alessandra; Pensotti, Valeria; Tommasi, Stefania; Peterlongo, Paolo; Weitzel, Jeffrey N; Osorio, Ana; Benitez, Javier; McGuffog, Lesley; Healey, Sue; Gerdes, Anne-Marie; Ejlertsen, Bent; Hansen, Thomas V O; Steele, Linda; Ding, Yuan Chun; Tung, Nadine; Janavicius, Ramunas; Goldgar, David E; Buys, Saundra S; Daly, Mary B; Bane, Anita; Terry, Mary Beth; John, Esther M; Southey, Melissa; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C; Ottini, Laura

    2016-02-09

    BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

  20. Prevalence of BRCA1 Mutations in Familial and Sporadic Greek Ovarian Cancer Cases

    Science.gov (United States)

    Stavropoulou, Alexandra V.; Fostira, Florentia; Pertesi, Maroulio; Tsitlaidou, Marianthi; Voutsinas, Gerassimos E.; Triantafyllidou, Olga; Bamias, Aristotelis; Dimopoulos, Meletios A.; Timotheadou, Eleni; Pectasides, Dimitrios; Christodoulou, Christos; Klouvas, George; Papadimitriou, Christos; Makatsoris, Thomas; Pentheroudakis, George; Aravantinos, Gerasimos; Karydakis, Vassilis; Yannoukakos, Drakoulis; Fountzilas, George; Konstantopoulou, Irene

    2013-01-01

    Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23–24 and exon 24). In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6%) of familial cancer cases and in 27/592 (4.6%) of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%). The majority of BRCA1 carriers (71.2%) presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer. PMID:23536787

  1. Prevalence of BRCA1 mutations in familial and sporadic greek ovarian cancer cases.

    Directory of Open Access Journals (Sweden)

    Alexandra V Stavropoulou

    Full Text Available Germline mutations in the BRCA1 and BRCA2 genes contribute to approximately 18% of hereditary ovarian cancers conferring an estimated lifetime risk from 15% to 50%. A variable incidence of mutations has been reported for these genes in ovarian cancer cases from different populations. In Greece, six mutations in BRCA1 account for 63% of all mutations detected in both BRCA1 and BRCA2 genes. This study aimed to determine the prevalence of BRCA1 mutations in a Greek cohort of 106 familial ovarian cancer patients that had strong family history or metachronous breast cancer and 592 sporadic ovarian cancer cases. All 698 patients were screened for the six recurrent Greek mutations (including founder mutations c.5266dupC, p.G1738R and the three large deletions of exon 20, exons 23-24 and exon 24. In familial cases, the BRCA1 gene was consequently screened for exons 5, 11, 12, 20, 21, 22, 23, 24. A deleterious BRCA1 mutation was found in 43/106 (40.6% of familial cancer cases and in 27/592 (4.6% of sporadic cases. The variant of unknown clinical significance p.V1833M was identified in 9/698 patients (1.3%. The majority of BRCA1 carriers (71.2% presented a high-grade serous phenotype. Identifying a mutation in the BRCA1 gene among breast and/or ovarian cancer families is important, as it enables carriers to take preventive measures. All ovarian cancer patients with a serous phenotype should be considered for genetic testing. Further studies are warranted to determine the prevalence of mutations in the rest of the BRCA1 gene, in the BRCA2 gene, and other novel predisposing genes for breast and ovarian cancer.

  2. BRCA1 Circos: a visualisation resource for functional analysis of missense variants.

    Science.gov (United States)

    Jhuraney, Ankita; Velkova, Aneliya; Johnson, Randall C; Kessing, Bailey; Carvalho, Renato S; Whiley, Phillip; Spurdle, Amanda B; Vreeswijk, Maaike P G; Caputo, Sandrine M; Millot, Gael A; Vega, Ana; Coquelle, Nicolas; Galli, Alvaro; Eccles, Diana; Blok, Marinus J; Pal, Tuya; van der Luijt, Rob B; Santamariña Pena, Marta; Neuhausen, Susan L; Donenberg, Talia; Machackova, Eva; Thomas, Simon; Vallée, Maxime; Couch, Fergus J; Tavtigian, Sean V; Glover, J N Mark; Carvalho, Marcelo A; Brody, Lawrence C; Sharan, Shyam K; Monteiro, Alvaro N

    2015-04-01

    Inactivating germline mutations in the tumour suppressor gene BRCA1 are associated with a significantly increased risk of developing breast and ovarian cancer. A large number (>1500) of unique BRCA1 variants have been identified in the population and can be classified as pathogenic, non-pathogenic or as variants of unknown significance (VUS). Many VUS are rare missense variants leading to single amino acid changes. Their impact on protein function cannot be directly inferred from sequence information, precluding assessment of their pathogenicity. Thus, functional assays are critical to assess the impact of these VUS on protein activity. BRCA1 is a multifunctional protein and different assays have been used to assess the impact of variants on different biochemical activities and biological processes. To facilitate VUS analysis, we have developed a visualisation resource that compiles and displays functional data on all documented BRCA1 missense variants. BRCA1 Circos is a web-based visualisation tool based on the freely available Circos software package. The BRCA1 Circos web tool (http://research.nhgri.nih.gov/bic/circos/) aggregates data from all published BRCA1 missense variants for functional studies, harmonises their results and presents various functionalities to search and interpret individual-level functional information for each BRCA1 missense variant. This research visualisation tool will serve as a quick one-stop publically available reference for all the BRCA1 missense variants that have been functionally assessed. It will facilitate meta-analysis of functional data and improve assessment of pathogenicity of VUS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Connecting protein and mRNA burst distributions for stochastic models of gene expression

    CERN Document Server

    Elgart, Vlad; Fenley, Andrew T; Kulkarni, Rahul V

    2011-01-01

    The intrinsic stochasticity of gene expression can lead to large variability in protein levels for genetically identical cells. Such variability in protein levels can arise from infrequent synthesis of mRNAs which in turn give rise to bursts of protein expression. Protein expression occurring in bursts has indeed been observed experimentally and recent studies have also found evidence for transcriptional bursting, i.e. production of mRNAs in bursts. Given that there are distinct experimental techniques for quantifying the noise at different stages of gene expression, it is of interest to derive analytical results connecting experimental observations at different levels. In this work, we consider stochastic models of gene expression for which mRNA and protein production occurs in independent bursts. For such models, we derive analytical expressions connecting protein and mRNA burst distributions which show how the functional form of the mRNA burst distribution can be inferred from the protein burst distributio...

  4. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze...... the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P......-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1...

  5. BRCA1 Accelerates CtIP-Mediated DNA-End Resection

    Directory of Open Access Journals (Sweden)

    Andrés Cruz-García

    2014-10-01

    Full Text Available DNA-end resection is a highly regulated and critical step in the response and repair of DNA double-strand breaks. In higher eukaryotes, CtIP regulates resection by integrating cellular signals via its posttranslational modifications and protein-protein interactions, including cell-cycle-controlled interaction with BRCA1. The role of BRCA1 in DNA-end resection is not clear. Here, we develop an assay to study DNA resection in higher eukaryotes at high resolution. We demonstrate that the BRCA1-CtIP interaction, albeit not essential for resection, modulates the speed at which this process takes place.

  6. Visfatin mRNA expression in human subcutaneous adipose tissue is regulated by exercise

    DEFF Research Database (Denmark)

    Frydelund-Larsen, Lone; Åkerström, Thorbjörn; Nielsen, Søren

    2006-01-01

    Visfatin [pre-beta-cell colony-enhancing factor (PBEF)] is a novel adipokine that is produced by adipose tissue, skeletal muscle, and liver and has insulin-mimetic actions. Regular exercise enhances insulin sensitivity. In the present study, we therefore examined visfatin mRNA expression...... by elevated levels of plasma visfatin. Recombinant human IL-6 infusion to mimic the exercise-induced IL-6 response (n = 6) had no effect on visfatin mRNA expression in adipose tissue compared with the effect of placebo infusion (n = 6). The finding that exercise enhances subcutaneous adipose tissue visfatin mRNA...... in abdominal subcutaneous adipose tissue and skeletal muscle biopsies obtained from healthy young men at time points 0, 3, 4.5, 6, 9, and 24 h in relation to either 3 h of ergometer cycle exercise at 60% of Vo(2 max) or rest. Adipose tissue visfatin mRNA expression increased threefold at the time points 3, 4...

  7. Breast cancer genes: beyond BRCA1 and BRCA2.

    Science.gov (United States)

    Filippini, Sandra E; Vega, Ana

    2013-06-01

    Breast cancer (BC) is a heterogeneous disease. The majority of breast cancer cases (about 70 percent) are considered sporadic. Familial breast cancer (about 30 percent of patients), often seen in families with a high incidence of BC, has been associated with a number of high-, moderate-, and low-penetrance susceptibility genes. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP1 (FANCJ), PALB2 (FANCN) and RAD51C (FANCO), are associated with moderate BC risk. Genome wide association studies (GWAS) in BC revealed a number of common low penetrance alleles associated with a slightly increased or decreased risk of BC. Currently, only high penetrance genes are used in clinical practice on a wide scale. Due to the development of next generation sequencing technologies, it is envisaged that all familial breast cancer genes will be included in the genetic test. However, additional research in clinical management of moderate and low-risk variants is needed before full implementation of multi-gene panel testing into clinical work-flows. In this review, we focus on the different components of familial breast cancer risk.

  8. Testosterone Regulates NUCB2 mRNA Expression in Male Mouse Hypothalamus and Pituitary Gland.

    Science.gov (United States)

    Seon, Sojeong; Jeon, Daun; Kim, Heejeong; Chung, Yiwa; Choi, Narae; Yang, Hyunwon

    2017-03-01

    Nesfatin-1/NUCB2 is known to take part in the control of the appetite and energy metabolism. Recently, many reports have shown nesfatin-1/NUCB2 expression and function in various organs. We previously demonstrated that nesfatin-1/NUCB2 expression level is higher in the pituitary gland compared to other organs and its expression is regulated by 17β-estradiol and progesterone secreted from the ovary. However, currently no data exist on the expression of nesfatin-1/NUCB2 and its regulation mechanism in the pituitary of male mouse. Therefore, we examined whether nesfatin-1/NUCB2 is expressed in the male mouse pituitary and if its expression is regulated by testosterone. As a result of PCR and western blotting, we found that a large amount of nesfatin-1/NUCB2 was expressed in the pituitary and hypothalamus. The NUCB2 mRNA expression level in the pituitary was decreased after castration, but not in the hypothalamus. In addition, its mRNA expression level in the pituitary was increased after testosterone treatment in the castrated mice, whereas, the expression level in the hypothalamus was significantly decreased after the treatment with testosterone. The in vitro experiment to elucidate the direct effect of testosterone on NUCB2 mRNA expression showed that NUCB2 mRNA expression was significantly decreased with testosterone in cultured hypothalamus tissue, but increased with testosterone in cultured pituitary gland. The present study demonstrated that nesfatin-1/NUCB2 was highly expressed in the male mouse pituitary and was regulated by testosterone. This data suggests that reproductive-endocrine regulation through hypothalamus-pituitary-testis axis may contribute to NUCB2 mRNA expression in the mouse hypothalamus and pituitary gland.

  9. Relationship between Fertilin _ mRNA expression and the fertilizing ...

    African Journals Online (AJOL)

    Moreover, defective protease can produce incomplete fertilin processing with improper maturation of sperm proteins. Here in this study showed possible direct role of fertilin- in fertilization and also in sperm morphology and hence sperm capicitation. Keywords: Fertilin expression, Infertility, Hormonal profile, Sperm function.

  10. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian...... cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15 patients with 7 different genomic rearrangements, including a BRCA1 exon 5-7 deletion with a novel breakpoint, a BRCA1...... exon 13 duplication, a BRCA1 exon 17-19 deletion, a BRCA1 exon 3-16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17-18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations...

  11. A high frequent BRCA1 founder mutation identified in the Greenlandic population

    DEFF Research Database (Denmark)

    Harboe, Theresa Larriba; Eiberg, Hans; Kern, Peder

    2009-01-01

    Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36-92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely...... the clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women...... carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths....

  12. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  13. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M

    2012-01-01

    Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number...... of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

  14. Screening of BRCA1 sequence variants within exon 11 by heteroduplex analysis

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2013-03-01

    Full Text Available Germ-line mutations of either BRCA1 or BRCA2 represents the major hereditary risk to breast and ovariancancer. Screening for mutations in these genes is now standard practice in molecular diagnosis, opening the way tooncogenetic counselling and follow-up. Because mutations in both BRCA1 and BRCA2 are distributed throughout theloci, accepted clinical protocols involve screening their entire coding regions. Systematic Sanger sequencing is time andmoney consuming. Therefore, a lot of pre-screening techniques evolved over time in order to identify anomalousamplicons prior to sequencing. Because BRCA mutations are always heterozygous, heteroduplex analysis proved to be asuitable pre-screening step. We previously implemented mismatch specific endonuclease heteroduplex analysis forBRCA1 exon7. Here we show the utility of the same method for mutations and SNPs found in BRCA1 exon 11

  15. A Genetic Screen for Genes Involved in BRCA 1 Tumor Suppressor Function

    National Research Council Canada - National Science Library

    Verma, Inder; Zhu, Quan

    2007-01-01

    Based on our initial screening, we have identified a number of candidates that are involved in DNA damage repair pathway mediated by BRCA1, which is an important aspect of tumor suppression of the molecular...

  16. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Science.gov (United States)

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  17. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries

    Science.gov (United States)

    Kwong, Ava; Shin, Vivian Y; Ho, John C W; Kang, Eunyoung; Nakamura, Seigo; Teo, Soo-Hwang; Lee, Ann S G; Sng, Jen-Hwei; Ginsburg, Ophira M; Kurian, Allison W; Weitzel, Jeffrey N; Siu, Man-Ting; Law, Fian B F; Chan, Tsun-Leung; Narod, Steven A; Ford, James M; Ma, Edmond S K; Kim, Sung-Won

    2015-01-01

    Approximately 5%–10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer. PMID:26187060

  18. BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela

    National Research Council Canada - National Science Library

    Lara, Karlena; Consigliere, Nigmet; Pérez, Jorge; Porco, Antonietta

    2012-01-01

    A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185...

  19. Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry.

    Science.gov (United States)

    Zhang, Jing; Fackenthal, James D; Zheng, Yonglan; Huo, Dezheng; Hou, Ningqi; Niu, Qun; Zvosec, Cecilia; Ogundiran, Temidayo O; Hennis, Anselm J; Leske, Maria Cristina; Nemesure, Barbara; Wu, Suh-Yuh; Olopade, Olufunmilayo I

    2012-07-01

    Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast

  20. Mechanism of Ovarian Epithelial Tumor Predisposition in Individuals Carrying Germline BRCA1 Mutations

    Science.gov (United States)

    2006-12-01

    cystadenomas , which are benign tumors made up of the same cell type as ovarian serous carcinomas. We confirmed that these tumors carried only the wild type... cystadenomas in strong support of our hypothesis. We proposed to elucidate the mechanism of tumor predisposition in this mouse model by identifying the...Maxson R, Dubeau L: Inactivation of Brca1 in mouse ovarian granulosa cells causes serous epithelial cystadenomas carrying functional Brca1alleles in

  1. BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses.

    Science.gov (United States)

    Brunsvold, Amy N; Wung, Shu-Fen; Merkle, Carrie J

    2005-12-01

    The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. Data sources include reviews and original research from scholarly journals and Internet sites. Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.

  2. Microglandular adenosis of the breast in a BRCA1 mutation carrier: radiological features

    Energy Technology Data Exchange (ETDEWEB)

    Sabate, J.M.; Gomez, A.; Torrubia, S. [Department of Diagnostic Radiology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Matias-Guiu, X. [Department of Pathology, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain); Alonso, C.; Pericay, C. [Department of Oncology, Hospital de Sant Pau, Universitat Autonoma de Barcelona, Sant Antoni M. Claret, 167, 08025 Barcelona (Spain); Diaz, O. [Department of Genetics, Hospital de Sant Pau, Universitat Autonoma de Barcelona (Spain)

    2002-06-01

    Microglandular adenosis is a very uncommon benign proliferative disorder of the breast that may mimic tubular carcinoma radiologically and pathologically. We describe the radiological features of this rare condition in a patient with BRCA 1 mutation. To our knowledge, this is the first case of microglandular adenosis reported in the radiology literature. The relationship between microglandular adenosis and malignancy and the association between BRCA 1 and proliferative benign disorders are also discussed. (orig.)

  3. BRCA1 and BRCA2 Germline Mutations Screening in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2010-01-01

    Full Text Available Background: Breast cancer is the leading cause of cancer death in women in Algeria. The contribution of BRCA1 and BRCA2 mutations to hereditary breast/ovarian cancer in Algerian population is largely unknown. Here, we describe analysis of BRCA1 and BRCA2 genes in 86 individuals from 70 families from an Algerian cohort with a personal and family history suggestive of genetic predisposition to breast cancer.

  4. Expression of connexin 37, 40, and 43 mRNA and protein in renal preglomerular arterioles

    DEFF Research Database (Denmark)

    Arensbak, B; Mikkelsen, Hanne Birte; Gustafsson, F

    2001-01-01

    arterioles in frozen sections was evaluated. SMC were isolated from kidneys using an iron oxide sieve method and explant technique. Total RNA from these cultures was tested by RT-PCR analysis for the expression of the three connexins mRNA. Using immunofluorescence we examined whether the expression pattern...

  5. Vascular Endothelial Growth Factor A Isoform mRNA Expression in Pediatric Acute Myeloid Leukemia

    NARCIS (Netherlands)

    Kruizinga, R. C.; de Jonge, H. J. M.; Kampen, K. R.; Walenkamp, A. M. E.; de Bont, E. S. J. M.

    In AML high VEGFA protein expression correlates with poor overall and relapse-free survival (OS/RFS). To date, the relevance of the various VEGFA isoforms is unclear. We determined VEGF121, VEGF145, VEGF148, VEGF165, VEGF183, and VEGF189 mRNA expression in pediatric AML samples and investigated the

  6. Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    Chiang, Huai-Chin; Elledge, Richard; Larson, Paula; Jatoi, Ismail; Li, Rong; Hu, Yanfen

    2015-01-01

    Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony-forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer.

  7. Synthetic lethality between CCNE1 amplification and loss of BRCA1.

    Science.gov (United States)

    Etemadmoghadam, Dariush; Weir, Barbara A; Au-Yeung, George; Alsop, Kathryn; Mitchell, Gillian; George, Joshy; Davis, Sally; D'Andrea, Alan D; Simpson, Kaylene; Hahn, William C; Bowtell, David D L

    2013-11-26

    High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.

  8. A Novel Pathogenic BRCA1 Splicing Variant Produces Partial Intron Retention in the Mature Messenger RNA

    Directory of Open Access Journals (Sweden)

    Maria Valeria Esposito

    2016-12-01

    Full Text Available About 10% of all breast cancers arise from hereditary mutations that increase the risk of breast and ovarian cancers; and about 25% of these are associated with the BRCA1 or BRCA2 genes. The identification of BRCA1/BRCA2 mutations can enable physicians to better tailor the clinical management of patients; and to initiate preventive measures in healthy carriers. The pathophysiological significance of newly identified variants poses challenges for genetic counseling. We characterized a new BRCA1 variant discovered in a breast cancer patient during BRCA1/2 screening by next-generation sequencing. Bioinformatic predictions; indicating that the variant is probably pathogenetic; were verified using retro-transcription of the patient’s RNA followed by PCR amplifications performed on the resulting cDNA. The variant causes the loss of a canonic donor splice site at position +2 in BRCA1 intron 21; and consequently the partial retention of 156 bp of intron 21 in the patient’s transcript; which demonstrates that this novel BRCA1 mutation plays a pathogenetic role in breast cancer. These findings enabled us to initiate appropriate counseling and to tailor the clinical management of this family. Lastly; these data reinforce the importance of studying the effects of sequence variants at the RNA level to verify their potential role in disease onset.

  9. Ovarian Cancer and BRCA1/2 Testing: Opportunities to improve clinical care and disease prevention

    Directory of Open Access Journals (Sweden)

    Katherine eKarakasis

    2016-05-01

    Full Text Available Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High grade serous ovarian cancer (HGSOC is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer, those at risk of developing cancer, but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many which are now being found to have BRCA1/2 involvement.

  10. Expression of hepcidin mRNA is uniformly suppressed in hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Tomosugi Naohisa

    2008-06-01

    Full Text Available Abstract Background The present study evaluated the expression of hepcidin mRNA in hepatocellular carcinoma (HCC. Methods Samples of cancerous and non-cancerous liver tissue were taken from 40 patients with HCC who underwent hepatectomy. Expression of hepcidin mRNA was evaluated by real-time PCR, and compared in tumors differing in their degree of differentiation, number of tumors, and vessel invasion. Correlations between hepcidin expression and the interval until HCC recurrence, and the serum concentration of hepcidin were evaluated, together with the expression of mRNAs for other iron metabolism molecules, ferroportin and transferrin receptor 2 (Trf2. Results Hepcidin mRNA expression in non-cancerous and cancerous tissues was 1891.8 (32.3–23187.4 and 53.4 (1.9–3185.8, respectively (P Conclusion Expression of hepcidin mRNA is strikingly suppressed in cancerous, but not in non-cancerous tissues, in patients with HCC, irrespective of ferroportin or Trf2 expression. Uniform suppression of hepcidin may be linked to the development of HCC.

  11. EXPRESSION OF AID-SPECIFIC mRNA IN PERIPHERAL BLOOD LYMPHOCYTES IN BRONCHIAL ASTHMA

    Directory of Open Access Journals (Sweden)

    V. N. Mineev

    2015-01-01

    Full Text Available The aim of this study was to evaluate a possible role of AID (AICDA – activation-induced (cytidine deaminase in the bronchial asthma (BA pathogenesis. Materials and methods. We have examined twelve healthy control persons, forty-two patients with allergic bronchial asthma (ABA and twenty-seven patients with non-allergic bronchial asthma (NABA. The AID mRNA expression was evaluated by means of RT-PCR. Results: AID mRNA was more significantly expressed in BA, than in healthy controls. Meanwhile, no significant differences were revealed between ABA and NABA groups. Correlation analysis of AID mRNA expression levels in peripheral blood lymphocytes has shown that CHε mRNA and total serum IgE revealed significant negative correlation, in the NABA group only. The levels of AID mRNA expression in peripheral blood lymphocytes exhibited positive and significant correlations with clinical characteristics, reflecting severity and stage of the disease, in BA patients. Moreover, a significant positive correlation was revealed with eosinophil contents in sputum. Conclusion. It was concluded that normal regulation of IgE class switching normally based on feedback regulation, was impaired in ABA but not affected in NABA. 

  12. Tuning protein expression using synonymous codon libraries targeted to the 5' mRNA coding region

    DEFF Research Database (Denmark)

    Goltermann, Lise; Borch Jensen, Martin; Bentin, Thomas

    2011-01-01

    sequence allowed tuning of protein expression over ~300-fold with preservation of amino acid identity. This approach is simple and should be generally applicable in bacteria. The data support that features in the 5' mRNA coding region near the AUG start codon are key in determining translation output......In bacteria, the 5' mRNA coding region plays an important role in determining translation output. Here, we report synthetic sequences that when placed in the 5'-mRNA coding region, leading to recombinant proteins containing short N-terminal extensions, virtually abolish, enhance or produce...... intermediate expression levels of green fluorescent protein in Escherichia coli. At least in one case, no apparent effect on protein stability was observed, pointing to RNA level effects as the principal reason for the observed expression differences. Targeting a synonymous codon library to the 5' coding...

  13. Eosinophil cationic protein mRNA expression in children with bronchial asthma.

    Science.gov (United States)

    Yu, H Y; Li, X Y; Cai, Z F; Li, L; Shi, X Z; Song, H X; Liu, X J

    2015-11-13

    Studies have shown that eosinophils are closely related to pathogenesis of bronchial asthma. Eosinophils release eosinophil cationic protein (ECP), which plays an important role in infection and allergic reactions. Serum ECP mRNA expression in children with bronchial asthma has not been adequately investigated. We analyzed serum ECP mRNA expression in 63 children with bronchial asthma and 21 healthy children by using reverse-transcriptase polymerase chain reaction to understand the role of ECP in children with bronchial asthma. The children with bronchial asthma were segregated into acute-phase and stable-phase groups, based on the severity of the illness. Serum ECP mRNA expression in children with bronchial asthma (0.375 ± 0.04) was significantly higher than that in healthy controls (0.20 ± 0.02; P bronchial asthma.

  14. Association of chemerin mRNA expression in human epicardial adipose tissue with coronary atherosclerosis

    Directory of Open Access Journals (Sweden)

    Wang Linjie

    2011-10-01

    Full Text Available Abstract Background Growing evidence suggests that epicardial adipose tissue (EAT may play a key role in the pathogenesis and development of coronary artery disease (CAD by producing several inflammatory adipokines. Chemerin, a novel adipokine, has been reported to be involved in regulating immune responses and glucolipid metabolism. Given these properties, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis. In this study, we sought to determine the relationship of chemerin expression in EAT and the severity of coronary atherosclerosis in Han Chinese patients. Methods Serums and adipose tissue biopsies (epicardial and thoracic subcutaneous were obtained from CAD (n = 37 and NCAD (n = 16 patients undergoing elective cardiac surgery. Gensini score was used to assess the severity of CAD. Serum levels of chemerin, adiponectin and insulin were measured by ELISA. Chemerin protein expression in adipose tissue was detected by immunohistochemistry. The mRNA levels of chemerin, chemR23, adiponectin and TNF-alpha in adipose tissue were detected by RT-PCR. Results We found that EAT of CAD group showed significantly higher levels of chemerin and TNF-alpha mRNA, and significantly lower level of adiponectin mRNA than that of NCAD patients. In CAD group, significantly higher levels of chemerin mRNA and protein were observed in EAT than in paired subcutaneous adipose tissue (SAT, whereas such significant difference was not found in NCAD group. Chemerin mRNA expression in EAT was positively correlated with Gensini score (r = 0.365, P P P P P P P > 0.05. Conclusions The expressions of chemerin mRNA and protein are significantly higher in EAT from patients with CAD in Han Chinese patients. Furthermore, the severity of coronary atherosclerosis is positive correlated with the level of chemerin mRNA in EAT rather than its circulating level.

  15. Germline BRCA1 mutations in patients from 84 families with breast and/or ovarian cancers in northern France.

    Science.gov (United States)

    Peyrat, J P; Vennin, P; Hornez, L; Fournier, J; Adenis, C; Bonneterre, J

    1998-02-01

    The BRCA1 gene modification is responsible for an autosomal dominant syndrome of inherited early onset breast and/or ovarian cancer. This gene is estimated to account for almost half of inherited breast cancers and three quarters of inherited breast/ovarian cancers. This suggests that about 1 in every 500 women may carry the BRCA1 mutation. The BRCA1 was isolated by positional cloning in 1994. More than 100 different mutations have been found in the germline of affected individuals. Using systematic sequencing, we looked at BRCA1 germline mutations in 84 patients treated at the Centre Oscar Lambret for breast and/or ovarian cancer who belonged to high-risk families. We found 39 mutations: 22 true mutations inducing modifications of the BRCA1 protein (BRCA1+), six mutations with unknown consequences on the BRCA1 protein, and eleven mutations corresponding to polymorphisms that had been described previously. All the BRCA1+ cases had a HPG3 tumour. The median age of discovery and the receptor positivity percentage are lower in hereditary breast cancer than in the standard population of the breast cancers treated in our centre. Conversely, most of the BRCA1+ patients are without node involvement. This shows that BRCA1 mutations are not always related to parameters thought to indicate a bad prognosis.

  16. BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny

    Science.gov (United States)

    Sotiropoulou, Panagiota A.; Karambelas, Andrea E.; Debaugnies, Maud; Candi, Aurelie; Bouwman, Peter; Moers, Virginie; Revenco, Tatiana; Rocha, Ana Sofia; Sekiguchi, Kiyotoshi; Jonkers, Jos; Blanpain, Cedric

    2013-01-01

    The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation of this process leads to cancer and aging. BRCA1 is a critical mediator of this process. Here, we performed conditional deletion of Brca1 during epidermal development and found that BRCA1 is specifically required for hair follicle (HF) formation and for development of adult HF stem cells (SCs). Mice deficient for Brca1 in the epidermis are hairless and display a reduced number of HFs that degenerate progressively. Surprisingly, the interfollicular epidermis and the sebaceous glands remain unaffected by Brca1 deletion. Interestingly, HF matrix transient amplifying progenitors present increased DNA damage, p53 stabilization, and caspase-dependent apoptosis compared with the interfollicular and sebaceous progenitors, leading to hyperproliferation, apoptosis, and subsequent depletion of the prospective adult HF SCs. Concomitant deletion of p53 and Brca1 rescues the defect of HF morphogenesis and loss of HF SCs. During adult homeostasis, BRCA1 is dispensable for quiescent bulge SCs, but upon their activation during HF regeneration, Brca1 deletion causes apoptosis and depletion of Brca1-deficient bulge SCs. Our data reveal a major difference in the requirement of BRCA1 between different types of epidermal SCs and progenitors and during the different activation stages of adult HF SCs. PMID:23271346

  17. Association of chemerin mRNA expression in human epicardial adipose tissue with coronary atherosclerosis.

    Science.gov (United States)

    Gao, Xiuying; Mi, Shuhua; Zhang, Fuzhuang; Gong, Fengying; Lai, Yongqiang; Gao, Feng; Zhang, Xiaoxia; Wang, Linjie; Tao, Hong

    2011-10-07

    Growing evidence suggests that epicardial adipose tissue (EAT) may play a key role in the pathogenesis and development of coronary artery disease (CAD) by producing several inflammatory adipokines. Chemerin, a novel adipokine, has been reported to be involved in regulating immune responses and glucolipid metabolism. Given these properties, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis. In this study, we sought to determine the relationship of chemerin expression in EAT and the severity of coronary atherosclerosis in Han Chinese patients. Serums and adipose tissue biopsies (epicardial and thoracic subcutaneous) were obtained from CAD (n = 37) and NCAD (n = 16) patients undergoing elective cardiac surgery. Gensini score was used to assess the severity of CAD. Serum levels of chemerin, adiponectin and insulin were measured by ELISA. Chemerin protein expression in adipose tissue was detected by immunohistochemistry. The mRNA levels of chemerin, chemR23, adiponectin and TNF-alpha in adipose tissue were detected by RT-PCR. We found that EAT of CAD group showed significantly higher levels of chemerin and TNF-alpha mRNA, and significantly lower level of adiponectin mRNA than that of NCAD patients. In CAD group, significantly higher levels of chemerin mRNA and protein were observed in EAT than in paired subcutaneous adipose tissue (SAT), whereas such significant difference was not found in NCAD group. Chemerin mRNA expression in EAT was positively correlated with Gensini score (r = 0.365, P correlation remained statistically significant (r = 0.357, P age, gender, BMI and waist circumference. Chemerin mRNA expression in EAT was also positively correlated with BMI (r = 0.305, P correlated with adiponectin mRNA expression in EAT (r = -0.322, P chemerin or adiponectin between the two groups. Likewise, neither serum chemerin nor serum adiponectin was associated with Gensini score (P > 0.05). The expressions of chemerin mRNA and

  18. Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

    OpenAIRE

    Garcia, Amandine I; Buisson, Monique; Damiola, Francesca; Tessereau, Chloé; Barjhoux, Laure; Verny-Pierre, Carole; Sornin, Valérie; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Caron, Olivier; Gautier-Villars, Marion; Coupier, Isabelle; Buecher, Bruno; Vennin, Philippe; Belotti, Muriel

    2016-01-01

    Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulati...

  19. Pathological complete response after cisplatin neoadjuvant therapy is associated with the downregulation of DNA repair genes in BRCA1-associated triple-negative breast cancers.

    Science.gov (United States)

    Domagala, Pawel; Hybiak, Jolanta; Rys, Janusz; Byrski, Tomasz; Cybulski, Cezary; Lubinski, Jan

    2016-10-18

    Pathologic complete response (pCR) after neoadjuvant chemotherapy is considered a suitable surrogate marker of treatment efficacy in patients with triple-negative breast cancers (TNBCs). However, the molecular mechanisms underlying pCR as a result of such treatment remain obscure. Using real-time PCR arrays we compared the expression levels of 120 genes involved in the main mechanisms of DNA repair in 43 pretreatment biopsies of BRCA1-associated TNBCs exhibiting pCR and no pathological complete response (non-pCR) after neoadjuvant chemotherapy with cisplatin. Altogether, 25 genes were significantly differentially expressed between tumors exhibiting pCR and non-pCR, and these genes were downregulated in the pCR group compared to the non-pCR group. A difference in expression level greater than 1.5-fold was detected for nine genes: MGMT, ERCC4, FANCB, UBA1, XRCC5, XPA, XPC, PARP3, and RPA1. The non-homologous end joining and nucleotide excision repair pathways of DNA repair showed the most significant relevance. Expression profile of DNA repair genes associated with pCR was different in the node-positive (20 genes with fold change >1.5) and node-negative (only 3 genes) subgroups. Although BRCA1 germline mutations are the principal defects in BRCA1-associated TNBC, our results indicate that the additional downregulation of other genes engaged in major pathways of DNA repair may play a decisive role in the pathological response of these tumors to cisplatin neoadjuvant chemotherapy. The results suggest that patients with node-positive BRCA1-associated TNBCs that do not exhibit pCR after cisplatin neoadjuvant chemotherapy may be candidates for subsequent therapy with PARP inhibitors, whereas UBA1 may be a potential therapeutic target in node-negative subgroup.

  20. Regulation and function of FTO mRNA expression in human skeletal muscle and subcutaneous adipose tissue

    DEFF Research Database (Denmark)

    Grunnet, Louise G; Nilsson, Emma; Ling, Charlotte

    2009-01-01

    Objective. Common variants in FTO (the fat-mass and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and non-genetic regulation of FTO mRNA in skeletal muscle......) and elderly (58-66 years) non-diabetic twins examined by a hyperinsulinemic euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n=226) and skeletal muscle biopsies (n=158). Results. Heritability of FTO expression in both tissues was low, and FTO...... expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle...

  1. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress.

    Science.gov (United States)

    Uematsu, M; Ohara, Y; Navas, J P; Nishida, K; Murphy, T J; Alexander, R W; Nerem, R M; Harrison, D G

    1995-12-01

    Shear stress enhances expression of Ca(2+)-calmodulin-sensitive endothelial cell nitric oxide synthase (ecNOS) mRNA and protein in bovine aortic endothelial cells (BAEC). The present studies were performed to investigate mechanisms responsible for regulation of ecNOS mRNA expression by shear stress and to determine if this induction of ecNOS mRNA is accompanied by an enhanced nitric oxide (NO) production. Shear stresses of 15 dyn/cm2 for 3-24 h resulted in a two- to threefold increase of ecNOS mRNA content quantified by Northern analysis in BAEC. Shear stresses (1.2-15 dyn/cm2) for 3 h resulted in an induction of ecNOS mRNA in a dose-dependent manner. In human aortic endothelial cells, shear stresses of 15 dyn/cm2 for 3 h also resulted in ecNOS mRNA induction. In BAEC, this induction in ecNOS mRNA was prevented by coincubation with actinomycin D (10 micrograms/ml). The K+ channel antagonist tetraethylammonium chloride (3 mM) prevented increase in ecNOS mRNA in response to shear stress. The ecNOS promotor contains putative binding domains for AP-1 complexes, potentially responsive to activation of protein kinase C (PKC). However, selective PKC inhibitor calphostin C (100 nM) did not inhibit ecNOS induction by shear stress. Finally, production of nitrogen oxides under both basal conditions and in response to the calcium ionophore A-23187 (1 microM) by BAEC exposed to shear stress was increased approximately twofold compared with cells not exposed to shear stress. These data suggest that ecNOS mRNA expression is regulated by K+ channel opening, but not by activation of PKC, and that shear not only enhances ecNOS mRNA expression but increases capacity of endothelial cells to release NO.

  2. Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer

    Directory of Open Access Journals (Sweden)

    Stenzl Arnulf

    2010-09-01

    Full Text Available Abstract Background Fibronectin 1 (FN1 is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of FN1 in development of renal cell cancer (RCC and to determine a prognostic relevance for optimal clinical management. Methods 212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of FN1 mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC as biological control and the ΔΔCt method for calculation of relative quantities. Results Mean tissue specific FN1 mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p FN1 expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10-5; Wilcoxon rank sum test. Patients with advanced disease had higher FN1 expression when compared to organ-confined disease (p FN1 mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test. There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA. Conclusions To our knowledge, this is the first study to show that FN1 mRNA expression is higher in RCC compared to normal renal tissue. FN1 mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.

  3. Tissue-specific mRNA expression profiling in grape berry tissues

    Directory of Open Access Journals (Sweden)

    Cramer Grant R

    2007-06-01

    Full Text Available Abstract Background Berries of grape (Vitis vinifera contain three major tissue types (skin, pulp and seed all of which contribute to the aroma, color, and flavor characters of wine. The pericarp, which is composed of the exocarp (skin and mesocarp (pulp, not only functions to protect and feed the developing seed, but also to assist in the dispersal of the mature seed by avian and mammalian vectors. The skin provides volatile and nonvolatile aroma and color compounds, the pulp contributes organic acids and sugars, and the seeds provide condensed tannins, all of which are important to the formation of organoleptic characteristics of wine. In order to understand the transcriptional network responsible for controlling tissue-specific mRNA expression patterns, mRNA expression profiling was conducted on each tissue of mature berries of V. vinifera Cabernet Sauvignon using the Affymetrix GeneChip® Vitis oligonucleotide microarray ver. 1.0. In order to monitor the influence of water-deficit stress on tissue-specific expression patterns, mRNA expression profiles were also compared from mature berries harvested from vines subjected to well-watered or water-deficit conditions. Results Overall, berry tissues were found to express approximately 76% of genes represented on the Vitis microarray. Approximately 60% of these genes exhibited significant differential expression in one or more of the three major tissue types with more than 28% of genes showing pronounced (2-fold or greater differences in mRNA expression. The largest difference in tissue-specific expression was observed between the seed and pulp/skin. Exocarp tissue, which is involved in pathogen defense and pigment production, showed higher mRNA abundance relative to other berry tissues for genes involved with flavonoid biosynthesis, pathogen resistance, and cell wall modification. Mesocarp tissue, which is considered a nutritive tissue, exhibited a higher mRNA abundance of genes involved in cell

  4. BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Ainur R. Akilzhanova

    2013-05-01

    Full Text Available Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05; higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation. 

  5. The mRNA expression of hTERT in human breast carcinomas correlates with VEGF expression

    Directory of Open Access Journals (Sweden)

    Kirkpatrick Katharine L

    2004-01-01

    Full Text Available Abstract Background Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase is the rate-limiting determinant of telomerase reactivation. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any correlation between hTERT and the negative prognostic indicators VEGF and PCNA by quantitatively measuring the mRNA expression of these genes in human breast cancer and in adjacent non-cancerous tissue (ANCT. Materials and methods RNA was extracted from 38 breast carcinomas and 40 ANCT. hTERT and VEGF165, VEGF189 and PCNA mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR and Taqman methodology. Results The level of expression of VEGF-165 and PCNA was significantly higher in carcinoma tissue than ANCT (p = 0.02. The ratio of VEGF165/189 expression was significantly higher in breast carcinoma than ANCT (p = 0.025. hTERT mRNA expression correlated with VEGF-189 mRNA (p = 0.008 and VEGF165 (p = 0.07. Conclusions hTERT mRNA expression is associated with the expression of the VEGF189 and 165 isoforms. This could explain the poorer prognosis reported in breast tumours expressing high levels of hTERT. The relative expression of the VEGF isoforms is significantly different in breast tumour to ANCT, and this may be important in breast carcinogenesis.

  6. Multiplex mRNA assay using electrophoretic tags for high-throughput gene expression analysis.

    Science.gov (United States)

    Tian, Huan; Cao, Liching; Tan, Yuping; Williams, Stephen; Chen, Lili; Matray, Tracy; Chenna, Ahmed; Moore, Sean; Hernandez, Vincent; Xiao, Vivian; Tang, Mengxiang; Singh, Sharat

    2004-09-08

    We describe a novel multiplexing technology using a library of small fluorescent molecules, termed eTag molecules, to code and quantify mRNA targets. eTag molecules, which have the same fluorometric property, but distinct charge-to-mass ratios possess pre-defined electrophoretic characteristics and can be resolved using capillary electrophoresis. Coupled with primary Invader mRNA assay, eTag molecules were applied to simultaneously quantify up to 44 mRNA targets. This multiplexing approach was validated by examining a panel of inflammation responsive genes in human umbilical vein endothelial cells stimulated with inflammatory cytokine interleukin 1beta. The laser-induced fluorescence detection and electrokinetic sample injection process in capillary electrophoresis allows sensitive quantification of thousands of copies of mRNA molecules in a reaction. The assay is precise, as evaluated by measuring qualified Z' factor, a dimensionless and simple characteristic for applications in high-throughput screening using mRNA assays. Our data demonstrate the synergy between the multiplexing capability of eTag molecules by sensitive capillary electrophoresis detection and the isothermal linear amplification characteristics of the Invader assay. eTag multiplex mRNA assay presents a unique platform for sensitive, high sample throughput and multiplex gene expression analysis.

  7. The potential lipolysis function of musclin and its mRNA expression ...

    African Journals Online (AJOL)

    Musclin is a newly discovered factor and its functions remain to be defined. This study investigated the tissue expression pattern of musclin gene and its potential effect on lipid metabolism. Musclin mRNA levels in adipose, muscle tissues and primary adipocytes were examined by quantitative PCR. The musclin gene ...

  8. PAX5α and PAX5β mRNA expression in breast Cancer: Relation to ...

    African Journals Online (AJOL)

    Background: Many studies evaluated the role of paired box gene 5 (PAX5) in breast cancer. However, few investigated PAX5α and PAX5β isoforms individually. Objective: The aim of the present study is to evaluate mRNA expression of PAX5α and PAX5β in breast cancer and assessing their underlying pathological roles ...

  9. Responses of mRNA expression of PepT1 in small intestine to ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-05-04

    May 4, 2009 ... tides by duodenal fistula, and changed the concentration of circulation peptides, and then monitored how mRNA expression of Pep T1 in duodenum, ileum and jejunum tissue was affected. MATERIALS AND METHODS. Experimental animals and diets. Sixteen Chinese Saanen dairy goats, with an average ...

  10. Lipoprotein Lipase mRNA expression in different tissues of farm ...

    African Journals Online (AJOL)

    Lipoprotein lipase (LPL) controls triacylglycerol partitioning between adipose tissues and muscles, so it is important enzyme for fattening of animals .The present work was planned to clarify the use of polymerase chain reaction (PCR) for detection of LPL mRNA expression in different tissues representing internal organs of ...

  11. EXPRESSION OF AHR AND ARNT MRNA IN CULTURED HUMAN ENDOMETRIAL EXPLANTS EXPOSED TO TCDD

    Science.gov (United States)

    Expression of AhR and ARNT mRNA in cultured human endometrial explants exposed to TCDD.Pitt JA, Feng L, Abbott BD, Schmid J, Batt RE, Costich TG, Koury ST, Bofinger DP.Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA.Endom...

  12. Expression of LDOC1 mRNA in leucocytes of patients with Down's ...

    Indian Academy of Sciences (India)

    Expression of LDOC1 mRNA in leucocytes of patients with Down's syndrome. Michele Salemi Concetta Barone Carmelo Romano Federico Ridolfo Roberto Salluzzo Francesco Scillato Cataldo Scavuzzo Filippo Caraci Aldo E. Calogero Corrado Romano Paolo Bosco. Research Note Volume 91 Issue 1 April 2011 pp 95-98 ...

  13. Differential expression of PARP1 mRNA in leucocytes of patients ...

    Indian Academy of Sciences (India)

    Differential expression of PARP1 mRNA in leucocytes of patients with Down's syndrome. Michele Salemi Concetta Barone Carmelo Romano Federico Ridolfo Elenora Gulotta Cataldo Scavuzzo Maria Grazia Salluzzo Mariaconcetta Giambirtone Filippo Caraci Carrado Romano Paolo Bosco. Research Note Volume 90 Issue ...

  14. Sheep oocyte expresses leptin and functional leptin receptor mRNA

    Directory of Open Access Journals (Sweden)

    Seyyed Jalil Taheri

    2016-09-01

    Conclusions: The result of present study reveals that leptin and its functional receptor (Ob-Rb mRNA are expressed in sheep oocyte and further studies should investigate the role(s of leptin on sheep oocyte physiology and embryo development.

  15. UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Dalgaard, Louise T., E-mail: ltd@ruc.dk [Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (United States); Department of Science, Systems and Models, Roskilde University (Denmark)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer UCP2 mRNA levels are decreased in islets of Langerhans from glucokinase deficient mice. Black-Right-Pointing-Pointer UCP2 mRNA up-regulation by glucose is dependent on glucokinase. Black-Right-Pointing-Pointer Absence of UCP2 increases GSIS of glucokinase heterozygous pancreatic islets. Black-Right-Pointing-Pointer This may protect glucokinase deficient mice from hyperglycemic damages. -- Abstract: Uncoupling Protein 2 (UCP2) is expressed in the pancreatic {beta}-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

  16. Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families.

    Science.gov (United States)

    Pietschmann, Andrea; Mehdipour, Parvin; Mehdipour, Parvin; Atri, Morteza; Hofmann, Wera; Hosseini-Asl, S Said; Scherneck, Siegfried; Mundlos, Stefan; Peters, Hartmut

    2005-08-01

    Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited breast cancer in Iran, we performed BRCA1/BRCA2 mutation analyses in ten Iranian high risk breast cancer families. This is the first study analysing the complete coding sequences of both genes that concerns the Iranian population. BRCA1/BRCA2 mutation detection included sequencing of the coding and the 3' and 5' untranslated regions. To detect large genomic rearrangements in the BRCA1 gene semi-quantitative multiplex PCR was performed. Two pathogenic mutations in the BRCA2 gene were detected: a novel deletion c.4415_4418delAGAA and a previously described insertion c.6033_6034insGT. In addition, one intronic variation g.5075-53C > T and a deletion/insertion g.*381_389del9ins29 in the 3' untranslated region of BRCA1 were found in two of the investigated families. Both sequence alterations were absent in an age matched Iranian control group. The BRCA2 homozygous variation p.N372H, previously associated with an increased risk for developing breast cancer, was not identified in this study. We did not detect large genomic rearrangements in BRCA1 in patients tested negatively for disease causing mutations in both genes by standard sequencing. At present, the BRCA2 mutations c.4415_4418delAGAA and c.6033_6034insGT have not been identified in any investigated population except the Iranian. Whether both mutations are specific for the Iranian population or a special subgroup remains to be investigated in larger studies. The absence of BRCA1 mutations in the analysed families may suggest that penetrance or prevalence of BRCA1 mutations may be lower in Iran.

  17. Differential gene expression using mRNA isolated on plastic microfluidic chips.

    Science.gov (United States)

    Bhattacharyya, Arpita; Klapperich, Catherine M

    2009-01-01

    Here we demonstrate the ability to perform differential gene expression experiments using messenger RNA (mRNA) isolated from crude cell lysates using a plastic microfluidic solid phase extraction column. The microfluidic columns (100microm by 100microm by 1.5 cm) were fabricated in a cyclic polyolefin by hot-embossing with an electroformed master-mold. The solid-phase consisted of a photopolymerized microporous monolith embedded with functional microparticles and covalently attached to the channel walls via photoinitiated grafting. For mRNA isolation from total RNA and direct mRNA isolation from cell lysates, oligo(dT) beads were embedded in the monolith. The extraction efficiency of the system is approximately 80% and the nucleic acid binding capacity of the silica solid-phase in this configuration is approximately 3.5 ng. The micro solid-phase was applied for the extraction and purification of mRNA from human liver total RNA and the isolation of mRNA from neonatal human dermal fibroblast cells (NHDF) and MCF7 breast cancer cell lysates. Differential gene expression between the two cell lines is demonstrated.

  18. High interleukin-6 mRNA expression is a predictor of relapse in colon cancer

    DEFF Research Database (Denmark)

    Olsen, Jesper; Kirkeby, Lene T.; Olsen, Jørgen

    2015-01-01

    Aim: To investigate the expression of interleukin-6 (IL6) in colon cancer tissue, and to examine if the risk of relapse is influenced by IL6 expression. Materials and Methods: Fresh-frozen biopsies from tumor and normal adjacent tissues were taken from patients with colon cancer during surgery...... and stored at −80°C. mRNA expression for interleukin-6 was evaluated with reverse transcription real time quantitative polymerase chain reaction. Survival analyses were carried-out using a Cox competing risk regression model. Results: IL6 mRNA was significantly more highly expressed in tumor tissue compared...... for clinicopathological characteristics (Hazard Ratio=2.16, 95% CI=1.07-4.40; pInterleukin-6 is up-regulated in colon cancer tissue at the transcriptional level and is significantly associated with increased risk of relapse....

  19. High interleukin-6 mRNA expression is a predictor of relapse in colon cancer

    DEFF Research Database (Denmark)

    Olsen, Jesper; Kirkeby, Lene T; Olsen, Jørgen

    2015-01-01

    AIM: To investigate the expression of interleukin-6 (IL6) in colon cancer tissue, and to examine if the risk of relapse is influenced by IL6 expression. MATERIALS AND METHODS: Fresh-frozen biopsies from tumor and normal adjacent tissues were taken from patients with colon cancer during surgery...... and stored at -80 °C. mRNA expression for interleukin-6 was evaluated with reverse transcription real time quantitative polymerase chain reaction. Survival analyses were carried-out using a Cox competing risk regression model. RESULTS: IL6 mRNA was significantly more highly expressed in tumor tissue compared...... for clinicopathological characteristics (Hazard Ratio=2.16, 95% CI=1.07-4.40; pInterleukin-6 is up-regulated in colon cancer tissue at the transcriptional level and is significantly associated with increased risk of relapse....

  20. The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor Development

    Science.gov (United States)

    2015-09-01

    Histo- and pathological analysis revealed that, unlike homogeneous and well differentiated T47D-Sh-Ctrl. mammary tumors, T47D-Sh-BRCA1 tumors were...AWARD NUMBER: W81XWH-13-1-0282 TITLE: The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and Tumor...2014 - 31 Aug 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER The Role of BRCA1 in Suppressing Epithelial-Mesenchymal Transition in Mammary Gland and

  1. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru

    Science.gov (United States)

    Abugattas, Julio; Llacuachaqui, Marcia; Allende, Yasser Sullcahuaman; Velásquez, Abelardo Arias; Velarde, Raúl; Cotrina, José; Garcés, Milko; León, Mauricio; Calderón, Gabriela; de la Cruz, Miguel; Mora, Pamela; Royer, Robert; Herzog, Josef; Weitzel, Jeffrey N; Narod, Steven A

    2014-01-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, thirteen deleterious mutations were identified (eleven in BRCA1 and two in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented seven of the eleven mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer. PMID:25256238

  2. BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

    Directory of Open Access Journals (Sweden)

    Reinhard Kalb

    2014-08-01

    Full Text Available The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3 ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.

  3. Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex

    Directory of Open Access Journals (Sweden)

    Otto J.P. Kyrieleis

    2016-12-01

    Full Text Available BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex.

  4. Screening of BRCA1/2 Mutations Using Direct Sequencing in Indonesian Familial Breast Cancer Cases.

    Science.gov (United States)

    Anwar, Sumadi Lukman; Haryono, Samuel J; Aryandono, Teguh; Datasena, I Gusti Bagus

    2016-01-01

    Breast cancer has emerged as the most prevalent cancer among women worldwide, including in Indonesia. The contribution of genes associated with high-risk breast-ovarian cancers, BRCA1 and BRCA2, in the Indonesian population is relatively unknown. We have characterized family history of patients with moderate- to high-risk of breast cancer predisposition in 26 unrelated cases from Indonesia for BRCA1/2 mutation analyses using direct sequencing. Known deleterious mutations were not found in either BRCA1 or BRCA2 genes. Seven variants in BRCA2 were documented in 10 of 26 patients (38%). All variants were categorized as unclassified (VUSs). Two synonymous variants, c.3623A>G and c.4035T>C, were found in 5 patients. One variant, c4600T>C, was found in a 38 year old woman with a family history of breast cancer. We have found 4 novel variants in BRCA2 gene including c.6718C>G, c.3281A>G, c.10176C>G, and c4490T>C in 4 unrelated patients, all of them having a positive family history of breast cancer. In accordance to other studies in Asian population, our study showed more frequent variants in BRCA2 compared to BRCA1. Further studies involving larger numbers of hereditary breast cancer patients are required to reveal contribution of BRCA1/2 mutations and/or other predisposing genes among familial breast cancer patients in Indonesia.

  5. Prevalance of BRCA1 and BRCA2 mutations in familial breast cancer patients in Lebanon

    Directory of Open Access Journals (Sweden)

    Jalkh Nadine

    2012-06-01

    Full Text Available Abstract Breast cancer is the most prevalent malignancy in women in Western countries, currently accounting for one third of all female cancers. Familial aggregation is thought to account for 5–10 % of all BC cases, and germline mutations in BRCA1 and BRCA2 account for less of the half of these inherited cases. In Lebanon, breast cancer represents the principal death-causing malignancy among women, with 50 % of the cases diagnosed before the age of 50 years. In order to study BRCA1/2 mutation spectra in the Lebanese population, 72 unrelated patients with a reported family history of breast and/or ovarian cancers or with an early onset breast cancer were tested. Fluorescent direct sequencing of the entire coding region and intronic sequences flanking each exon was performed. A total of 38 BRCA1 and 40 BRCA2 sequence variants were found. Seventeen of them were novel. Seven confirmed deleterious mutations were identified in 9 subjects providing a frequency of mutations of 12.5 %. Fifteen variants were considered of unknown clinical significance according to BIC and UMD-BRCA1/BRCA2 databases. In conclusion, this study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer.

  6. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F

    2007-01-01

    oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk...... of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full...... was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk...

  7. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Peru.

    Science.gov (United States)

    Abugattas, J; Llacuachaqui, M; Allende, Y Sullcahuaman; Velásquez, A Arias; Velarde, R; Cotrina, J; Garcés, M; León, M; Calderón, G; de la Cruz, M; Mora, P; Royer, R; Herzog, J; Weitzel, J N; Narod, S A

    2015-10-01

    The prevalence of BRCA1 and BRCA2 mutations among breast cancer patients in Peru has not yet been explored. We enrolled 266 women with breast cancer from a National cancer hospital in Lima, Peru, unselected for age or family history. DNA was screened with a panel of 114 recurrent Hispanic BRCA mutations (HISPANEL). Among the 266 cases, 13 deleterious mutations were identified (11 in BRCA1 and 2 in BRCA2), representing 5% of the total. The average age of breast cancer in the mutation-positive cases was 44 years. BRCA1 185delAG represented 7 of 11 mutations in BRCA1. Other mutations detected in BRCA1 included: two 2080delA, one 943ins10, and one 3878delTA. The BRCA2 3036del4 mutation was seen in two patients. Given the relatively low cost of the HISPANEL test, one should consider offering this test to all Peruvian women with breast or ovarian cancer. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Weischer, Maren; Freiberg, Jacob Johannes

    2009-01-01

    PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling.......3 in the prospective study, and above 1.2 to 3.2 in the case-control study. CONCLUSIONS: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer......, as their impact on risk of breast and ovarian cancer is unclear. EXPERIMENTAL DESIGN: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met...

  9. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.

    Science.gov (United States)

    Leung, Justin W C; Makharashvili, Nodar; Agarwal, Poonam; Chiu, Li-Ya; Pourpre, Renaud; Cammarata, Michael B; Cannon, Joe R; Sherker, Alana; Durocher, Daniel; Brodbelt, Jennifer S; Paull, Tanya T; Miller, Kyle M

    2017-02-01

    Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome. We show that ZMYM3 links the HR factor BRCA1 to damaged chromatin through specific interactions with components of the BRCA1-A subcomplex, including ABRA1 and RAP80. By regulating ABRA1 recruitment to damaged chromatin, ZMYM3 facilitates the fine-tuning of BRCA1 interactions with DNA damage sites and chromatin. Consistent with a role in regulating BRCA1 function, ZMYM3 deficiency results in impaired HR repair and genome instability. Thus, our work identifies a critical chromatin-binding DNA damage response factor, ZMYM3, which modulates BRCA1 functions within chromatin to ensure the maintenance of genome integrity. © 2017 Leung et al.; Published by Cold Spring Harbor Laboratory Press.

  10. Peripheral Mononuclear Cell Resistin mRNA Expression Is Increased in Type 2 Diabetic Women

    Directory of Open Access Journals (Sweden)

    Panayoula C. Tsiotra

    2008-01-01

    Full Text Available Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P=.05. Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6 were all significantly higher in DM2 compared to control women (P<.001. The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P=.051, and overall, they correlated significantly with BMI (r=0.406, P=.010 and waist circumference (r=0.516, P=.003, but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.

  11. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Kuchenbaecker, Karoline B; Hopper, John L; Barnes, Daniel R; Phillips, Kelly-Anne; Mooij, Thea M; Roos-Blom, Marie-José; Jervis, Sarah; van Leeuwen, Flora E; Milne, Roger L; Andrieu, Nadine; Goldgar, David E; Terry, Mary Beth; Rookus, Matti A; Easton, Douglas F; Antoniou, Antonis C; BRCA1 and BRCA2 Cohort Consortium; McGuffog, Lesley; Evans, D Gareth; Barrowdale, Daniel; Frost, Debra; Adlard, Julian; Ong, Kai-Ren; Izatt, Louise; Tischkowitz, Marc; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Nogues, Catherine; Lasset, Christine; Stoppa-Lyonnet, Dominique; Fricker, Jean-Pierre; Faivre, Laurence; Berthet, Pascaline; Hooning, Maartje J; van der Kolk, Lizet E; Kets, Carolien M; Adank, Muriel A; John, Esther M; Chung, Wendy K; Andrulis, Irene L; Southey, Melissa; Daly, Mary B; Buys, Saundra S; Osorio, Ana; Engel, Christoph; Kast, Karin; Schmutzler, Rita K; Caldes, Trinidad; Jakubowska, Anna; Simard, Jacques; Friedlander, Michael L; McLachlan, Sue-Anne; Machackova, Eva; Foretova, Lenka; Tan, Yen Y; Singer, Christian F; Olah, Edith; Gerdes, Anne-Marie; Arver, Brita; Olsson, Håkan

    2017-06-20

    The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44

  12. Tolerance for uncertainty and perceived risk among women receiving uninformative BRCA1/2 test results.

    Science.gov (United States)

    O'Neill, Suzanne C; DeMarco, Tiffani; Peshkin, Beth N; Rogers, Sarah; Rispoli, Jessica; Brown, Karen; Valdimarsdottir, Heiddis; Schwartz, Marc D

    2006-11-15

    Women who receive uninformative BRCA1/2 genetic test results face ongoing uncertainty about their future cancer risks. This article prospectively examined the influence of intolerance for uncertainty and perceived breast cancer risk on psychological distress following the receipt of uninformative BRCA1/2 test results. Sixty-four women who received uninformative BRCA1/2 mutation test results completed measures of Intolerance for Uncertainty, perceived breast cancer risk, and measures of cancer-related, genetic testing, and general distress. Cancer-related (DeltaR(2) = 0.18, P uncertainty at 1 month post-disclosure. The interaction of intolerance for uncertainty and breast cancer perceived risk predicted cancer-related (DeltaR(2) = 0.10, P uncertainty, suggesting that those who have difficulty coping with their ambiguous risk are at risk for long-term distress. The clinical and research implications of these results are discussed. (c) 2006 Wiley-Liss, Inc.

  13. BRCA 1/2-mutation related and sporadic breast and ovarian cancers: More alike than different

    Directory of Open Access Journals (Sweden)

    Melissa A. Burgess

    2014-02-01

    Full Text Available No longer is histology solely predictive of cancer treatment and outcome. There is an increasing influence of tumor genomic characteristics on therapeutic options. Both breast and ovarian cancers are at higher risk of development in patients with BRCA 1/2-germline mutations. Recent data from the Cancer Genome Atlas (TCGA and others have shown a number of genomic similarities between triple negative breast cancers and ovarian cancers. Recently, poly (ADP-ribose polymerase (PARP inhibitors have shown promising activity in hereditary BRCA 1/2-mutated and sporadic breast and ovarian cancers. In this review, we will summarize the current literature regarding the genomic and phenotypic similarities between BRCA 1/2-mutation related cancers, sporadic triple negative breast cancers, and sporadic ovarian cancers. We will also review phase I, II, and III data using PARP inhibitors for these malignancies and compare and contrast the results with respect to histology.

  14. Maternal mRNA expression levels of H19 are inversely associated with risk of macrosomia.

    Science.gov (United States)

    Jiang, Hua; Yu, Yang; Xun, Pengcheng; Zhang, Jun; Luo, Guanghua; Wang, Qiuwei

    2014-06-29

    To investigate the associations between the mRNA levels of H19 in term placenta and risk of macrosomia. Term placentas were collected from 37 macrosomia and 37 matched neonates with normal birth weight (controls) born in Changzhou Women and Children Health Hospital, Jiangsu province, P. R. China from March 1 to June 30, 2008. The mRNA levels of H19 in those placentas were measured by real-time polymerase chain reaction (PCR). Simple and multiple logistic regression models were used to explore the risk factors in the development of macrosomia. All analyses were performed using Stata 10.0 (StataCorp, College Station, Texas, USA). The average H19 mRNA level of the macrosomia group was 1.450 ±0.456 while in the control group it was 2.080 ±1.296. Based on the result of Student's t test, there was a significant difference in H19 mRNA level between the macrosomia group and the control group (p = 0.008). After controlling for potential confounders, the multivariable adjusted odds ratio (OR) of macrosomia for those in the highest tertile of H19 mRNA level was 0.12 (95% CI: 0.02-0.59) when compared to those in the lowest tertile (p for linear trend = 0.009). The term placental H19 mRNA levels were inversely related to the occurrence of macrosomia. Our findings suggest that the low expression of H19 mRNA may contribute to the development of macrosomia.

  15. Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Janssen, Claas; Schmalbach, Sonja; Boeselt, Sebastian; Sarlette, Alexander; Dengler, Reinhard; Petri, Susanne

    2010-06-01

    Histone deacetylases (HDACs) are important regulators of gene expression and cell differentiation. The HDAC inhibitors have recently been considered as potential novel neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors that may cause a variety of toxic side effects. The mRNA expression levels of the HDAC isoforms HDACs 1 to 11 have previously been characterized in rat brain but have not been studied in human tissue. Using in situ hybridization histochemistry and immunohistochemistry we assessed the distribution and expression levels of HDACs 1to 11 in postmortem ALS and control brain and spinal cord specimens (n = 6 cases each) to determine alterations in the mRNA expression pattern that could provide a basis for disease-specific therapies. We found a reduction of HDAC 11 mRNA and increased HDAC 2 levels in ALS brain and spinal cord compared with controls. A more precise knowledge of the disease-related expression pattern could lead to the development of more specific pharmacotherapeutic approaches.

  16. Rhythmic expression of Nocturnin mRNA in multiple tissues of the mouse

    Directory of Open Access Journals (Sweden)

    Green Carla B

    2001-05-01

    Full Text Available Abstract Background Nocturnin was originally identified by differential display as a circadian clock regulated gene with high expression at night in photoreceptors of the African clawed frog, Xenopus laevis. Although encoding a novel protein, the nocturnin cDNA had strong sequence similarity with a C-terminal domain of the yeast transcription factor CCR4, and with mouse and human ESTs. Since its original identification others have cloned mouse and human homologues of nocturnin/CCR4, and we have cloned a full-length cDNA from mouse retina, along with partial cDNAs from human, cow and chicken. The goal of this study was to determine the temporal pattern of nocturnin mRNA expression in multiple tissues of the mouse. Results cDNA sequence analysis revealed a high degree of conservation among vertebrate nocturnin/CCR4 homologues along with a possible homologue in Drosophila. Northern analysis of mRNA in C3H/He and C57/Bl6 mice revealed that the mNoc gene is expressed in a broad range of tissues, with greatest abundance in liver, kidney and testis. mNoc is also expressed in multiple brain regions including suprachiasmatic nucleus and pineal gland. Furthermore, mNoc exhibits circadian rhythmicity of mRNA abundance with peak levels at the time of light offset in the retina, spleen, heart, kidney and liver. Conclusion The widespread expression and rhythmicity of mNoc mRNA parallels the widespread expression of other circadian clock genes in mammalian tissues, and suggests that nocturnin plays an important role in clock function or as a circadian clock effector.

  17. Orosomucoid serum concentrations and fat depot-specific mRNA and protein expression in humans.

    Science.gov (United States)

    Alfadda, Assim A; Fatma, Sumbul; Chishti, M Azhar; Al-Naami, Mohammed Y; Elawad, Ruba; Mendoza, Carmen Deanna O; Jo, Hyunsun; Lee, Yun Sok

    2012-01-01

    Obesity is associated with chronic low-grade inflammation, which contributes to systemic metabolic irregularities and obesity-linked metabolic disorders. Orosomucoid (ORM), an acute phase reactant protein, was shown to be produced in response to metabolic and inflammatory signals in the adipose tissue of obese mice, which protects them from severe inflammation and subsequent metabolic dysfunction. In this study, we examined whether there are site-specific differences between visceral and subcutaneous adipose tissue (VAT and SAT, respectively) ORM gene and protein expression from individuals with a wide range of obesity and the relationship between expressed and circulating ORM levels and measures of adiposity, insulin resistance, and pro- and anti-inflammatory markers and adipokines. The level of circulating ORM correlated positively with BMI, body fat mass, and serum leptin. It also correlated with fasting insulin, HOMA-IR values and C-reactive protein in men. There were no site-specific differences in ORM mRNA and protein expression between VAT and SAT, nor did we find a relationship between circulating ORM levels and its mRNA expression in either fat depot. We found that ORM mRNA expression correlated with mRNA expression of TNF-α, IL-6, and adiponectin in VAT, and with TNF-α and adiponectin in SAT. These observations are the first description linking adipose tissue ORM and pro- and anti-inflammatory molecules in humans. The close links of ORM and measures of adiposity, insulin resistance, and adipose tissue inflammation in humans reinforce previous experimental data and warrant further studies to explore a possible role of ORM in the pathogenesis of obesity-associated metabolic derangements.

  18. Modulation of IFNAR1 mRNA expression in multiple sclerosis patients.

    Science.gov (United States)

    Serana, Federico; Sottini, Alessandra; Ghidini, Claudia; Zanotti, Cinzia; Capra, Ruggero; Cordioli, Cinzia; Caimi, Luigi; Imberti, Luisa

    2008-06-15

    Interferon-beta receptor (IFNAR) is composed of 2 subunits, IFNAR1 and IFNAR2, the latter of which is expressed as functional (IFNAR2.2), non-functional (IFNAR2.1) and soluble (IFNAR2.3) isoform. Real-Time PCR analysis of mRNA for all IFNAR components in multiple sclerosis patients naïve for therapy and undergoing long-term treatment with interferon-beta shows that IFNAR1 mRNA level is lower than in healthy controls. If long-term treated patients are divided according to the production of mRNA for Myxovirus protein-A, a marker of interferon-beta bioactivity, IFNAR1 mRNA reaches the values observed in controls only in Myxovirus protein-A-induced patients. Since chronic cell stimulation by interferon-beta induces IFNAR protein down-regulation, we suggest that the increase of IFNAR1 mRNA might serve as a mechanism for counterbalancing the loss of protein receptor, enhancing, at least in this sub-group of patients, cell responsiveness to interferon-beta.

  19. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    Science.gov (United States)

    2009-01-01

    Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer. PMID:19298662

  20. Breast imaging findings in women with BRCA1- and BRCA2-associated breast carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, L.J.; Evans, A.J. E-mail: aevans@ncht.trent.nhs.uk; Wilson, A.R.M.; Scott, N.; Cornford, E.J.; Pinder, S.E.; Khan, H.N.; Macmillan, R.D

    2004-10-01

    AIM: To document the breast imaging findings of women with BRCA1 and BRCA2-associated breast carcinoma. MATERIALS AND METHODS: Family history clinic records identified 18 BRCA1 and 10 BRCA2 cases who collectively were diagnosed with 27 invasive breast carcinomas and four ductal carcinoma in situ (DCIS) lesions. All underwent pre-operative imaging (29 mammogram and 22 ultrasound examinations). All invasive BRCA-associated breast carcinoma cases were compared with age-matched cases of sporadic breast carcinoma. RESULTS: Within the BRCA cases the age range was 26-62 years, mean 36 years. Two mammograms were normal and 27 (93%) abnormal. The most common mammographic features were defined mass (63%) and microcalcifications (37%). Thirty-four percent of women had a dense mammographic pattern, 59% mixed and 7% fatty. Ultrasound was performed in 22 patients and in 21 (95%) indicated a mass. This was classified as benign in 24%, indeterminate in 29% and malignant in 48%. Mammograms of BRCA1-associated carcinomas more frequently showed a defined mass compared with BRCA2-associated carcinomas, 72 versus 36% (73% control group) whilst mammograms of BRCA2-associated carcinomas more frequently showed microcalcification, 73 versus 12% (8% control group; p<0.001). Thirty-six percent of the BRCA2-associated carcinomas were pure DCIS while none of the BRCA1 associated carcinomas were pure DCIS (p=0.004). Of those patients undergoing regular mammographic screening, 100% of BRCA2-associated carcinomas were detected compared with 75% of BRCA1-associated carcinomas. CONCLUSION: These data suggest that the imaging findings of BRCA1 and BRCA2-associated carcinomas differ from each other and from age-matched cases of sporadic breast carcinoma.

  1. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    DeSai Damini

    2009-03-01

    Full Text Available Abstract Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2. The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE. All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%. Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

  2. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity

    DEFF Research Database (Denmark)

    Tacconi, Eliana Mc; Lai, Xianning; Folio, Cecilia

    2017-01-01

    dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient...... FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde...

  3. Consanguinity Protecting Effect Against Breast Cancer among Tunisian Women: Analysis of BRCA1 Haplotypes.

    Science.gov (United States)

    Medimegh, Imen; Troudi, Wafa; Omrane, Ines; Ayari, Hajer; Uhrhummer, Nancy; Majoul, Hamdi; Benayed, Farhat; Mezlini, Amel; Bignon, Yves-Jean; Sibille, Catherine; Elgaaied, Amel Benammar

    2015-01-01

    The purpose of this study is to assess the effect of consanguinity on breast cancer incidence in Tunisia. We conducted a case-control study to evaluate the involvement of heterozygote and homozygote haplotypes of BRCA1 gene SNPs according to consanguinity among 40 cases of familial breast cancer, 46 cases with sporadic breast cancer and 34 healthy controls. We showed significant difference in consanguinity rate between breast cancer patients versus healthy controls P = 0.001. Distribution of homozygous BRCA1 haplotypes among healthy women versus breast cancer patients was significantly different; p=0.02. Parental consanguinity seems to protect against breast cancer in the Tunisian population.

  4. HEREDITARY CHARACTERISTICS BRCA1 5382INSC/СHEK2/BLM-ASSOCIATED BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Е. М. Bit-Sava

    2014-01-01

    Full Text Available The hereditary breast cancer (HBC occurs in 5–10 % of all cases of breast cancer. The mutations in the genes of high penetrance – BRCA1, BRCA2 is mainly the reason HBC. In the study presented the features of HBC (age of onset of the disease, cancer family history, primary tumor process multiple character. Depending on the presence of mutations BRCA1 5382insC, BLM, CHEK2 carried out a comparative analysis of the occurrence of hereditary characteristics in breast cancer patients.

  5. The Role of BRCA1/BARD1 Heterodimers in the Mitosis-Interphase Transition

    Science.gov (United States)

    2007-05-01

    et al., 2001; Mallery, et al., 2002; Sato, et al., 2004; Starita , et al., 2004; Yu, et al., 2006). Despite extensive studies, it is still unclear...amplification in giant-cell tumor of bone: Array CGH, FISH, and association with outcome. Genes Chromosomes Cancer 45, 957-966. Starita , L. M., Machida, Y...al., 2004; Starita et al., 2004; Yu et al., 2006). Whether any of these proteins is a physio- logical BRCA1/BARD1 substrate is unknown. BRCA1 and BARD1

  6. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier.

    Science.gov (United States)

    Osgood, Doreen; Miller, Miles C; Messier, Arthur A; Gonzalez, Liliana; Silverberg, Gerald D

    2017-09-01

    Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. mRNA expression pattern of gonadotropin receptors in bovine follicular cysts.

    Science.gov (United States)

    Marelli, Belkis E; Diaz, Pablo U; Salvetti, Natalia R; Rey, Florencia; Ortega, Hugo H

    2014-12-01

    Follicular growth and steroidogenesis are dependent on gonadotropin binding to their receptors in granulosa and theca cells of ovarian follicles. The aim of the present study was to evaluate the expression patterns of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) in ovarian follicular structures from cows with cystic ovarian disease (COD) as compared with those of regularly cycling cows. Relative real-time RT-PCR analysis showed that the expression of FSHR mRNA in granulosa cells was highest in small antral follicles, then decreased significantly as follicles increased in size, and was lowest in cysts. FSHR mRNA was not detected in the theca cells of any follicular category, including cysts. LHCGR mRNA expression in granulosa cells was significantly higher in large antral follicles than in cysts, and not detected in granulosa cells of small and medium antral follicles. In theca cells, the expression level of LHCGR mRNA in medium antral follicles was higher than in small and large antral follicles, whereas that in follicular cysts it was similar to those in small and medium antral follicles, but higher than that in large antral follicles. Our findings provide evidence that there is an altered gonadotropin receptor expression in bovine cystic follicles, and suggest that in conditions characterized by altered ovulation, such as COD, changes in the signaling system of gonadotropins may play a fundamental role in their pathogenesis. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Local IGFBP-3 mRNA expression, apoptosis and risk of colorectal adenomas

    Directory of Open Access Journals (Sweden)

    Omofoye Oluwaseun

    2008-05-01

    Full Text Available Abstract Background IGF binding protein-3 (IGFBP-3 regulates the bioavailability of insulin-like growth factors I and II, and has both anti-proliferative and pro-apoptotic properties. Elevated plasma IGFBP-3 has been associated with reduced risk of colorectal cancer (CRC, but the role of tissue IGFBP-3 is not well defined. We evaluated the association between tissue or plasma IGFBP-3 and risk of colorectal adenomas or low apoptosis. Methods Subjects were consenting patients who underwent a clinically indicated colonoscopy at UNC Hospitals and provided information on diet and lifestyle. IGFBP-3 mRNA in normal colon was assessed by real time RT-PCR. Plasma IGFBP-3 was measured by ELISA and apoptosis was determined by morphology on H & E slides. Logistic regression was used to compute odds ratio (OR and 95% confidence intervals. Results We observed a modest correlation between plasma IGFBP-3 and tissue IGFBP-3 expression (p = 0.007. There was no significant association between plasma IGFBP-3 and adenomas or apoptosis. Tissue IGFBP-3 mRNA expression was significantly lower in cases than controls. Subjects in the lowest three quartiles of tissue IGFBP-3 gene expression were more likely to have adenomas. Consistent with previous reports, low apoptosis was significantly associated with increased risk of adenomas (p = 0.003. Surprisingly, local IGFBP-3 mRNA expression was inversely associated with apoptosis. Conclusion Low expression of IGFBP-3 mRNA in normal colonic mucosa predicts increased risk of adenomas. Our findings suggest that local IGFBP-3 in the colon may directly increase adenoma risk but IGFBP-3 may act through a pathway other than apoptosis to influence adenoma risk.

  9. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, Anna Marie; Couch, Fergus J.; Barrowdale, Daniel; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Robson, Mark; Sherman, Mark; Spurdle, Amanda B.; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Janavicius, Ramunas; Hansen, Thomas vO; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Muñoz-Repeto, Iván; Durán, Mercedes; Godino, Javier; Pertesi, Maroulio; Benítez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Gómez García, Encarna B.; Nelen, Marcel R.; Kets, C. Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M. A.; van der Luijt, Rob B.; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J. Louise; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E.; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K.; Schmutzler, Rita K.; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schäfer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Hardouin, Agnès; Berthet, Pascaline; Muller, Danièle; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B.; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo; Weitzel, Jeffrey N.; Lynch, Henry T.; Ganz, Patricia A.; Tomlinson, Gail E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F.; tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L.; Greene, Mark H.; Imyanitov, Evgeny; O'Malley, Frances P.; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E.; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L.; Beattie, Mary; Pharoah, Paul D. P.; Moysich, Kirsten B.; Nathanson, Katherine L.; Karlan, Beth Y.; Gross, Jenny; John, Esther M.; Daly, Mary B.; Buys, Saundra M.; Southey, Melissa C.; Hopper, John L.; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F.; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F.; Andrulis, Irene L.; Antoniou, Antonis C.; Ellis, Steve; Fineberg, Elena; Platte, Radka; Miedzybrodzka, Zosia; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai-Ren; Hoffman, Jonathan; James, Margaret; Paterson, Joan; Downing, Sarah; Taylor, Amy; Rogers, T.; Kennedy, John M.; Barton, David; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Jacobs, Chris; Langman, Caroline; Whaite, Anna; Chu, Carol; Miller, Julie; Ellis, Ian; Taylor, Jane; Male, Alison; Berlin, Cheryl; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; D'Mello, Lucia; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Mitra, Anita; Robertson, Lisa; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Barjhoux, Laure; Verny-Pierre, Carole; Giraud, Sophie; Gauthier-Villars, Marion; Buecher, Bruno; Houdayer, Claude; Belotti, Muriel; Tirapo, Carole; de Pauw, Antoine; Roussy, Gustave; Bressac-de-Paillerets, Brigitte; Remenieras, Audrey; Byrde, Véronique; Caron, Olivier; Lenoir, Gilbert; Bignon, Yves-Jean; Uhrhammer, Nancy; Bérard, Léon; Lasset, Christine; Bonadona, Valérie; Baclesse, François; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Peyrat, Jean-Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Demange, Liliane; Nogues, Catherine; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Ferrer, Sandra Fert; Lacassagne, Antoine; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Snyder, Carrie L.; Hogervorst, F. B. L.; Verhoef, S.; Verheus, M.; van 't Veer, L. J.; van Leeuwen, F. E.; Collée, M.; van den Ouweland, A. M. W.; Jager, A.; Hooning, M. J.; van Asperen, C. J.; Wijnen, J. T.; Vreeswijk, M. P.; Tollenaar, R. A.; Devilee, P.; Ligtenberg, M. J.; Hoogerbrugge, N.; Ausems, M. G.; Aalfs, C. M.; Gille, J. J. P.; Waisfisz, Q.; Gomez-Garcia, E. B.; van Roozendaal, C. E.; Blok, Marinus J.; Caanen, B.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; Vasen, H. F.; Nordling, Margareta; Bergman, Annika; Einbeigi, Zakaria; Liedgren, Sigrun; Borg, Åke; Loman, Niklas; Olsson, Håkan; Kristoffersson, Ulf; Jernström, Helena; Harbst, Katja; Lindblom, Annika; Liljegren, Annelie; Barbany-Bustinza, Gisela; Rantala, Johanna; Melin, Beatrice; Grönberg, Henrik; Stattin, Eva-Lena; Emanuelsson, Monica; Ehrencrona, Hans; Rosenquist, Richard; Dahl, Niklas

    2011-01-01

    Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2

  10. [Expression of PEPT2 mRNA in lung tissue of rats with pulmonary fibrosis].

    Science.gov (United States)

    Li, Li; Wang, Dianhua; Zhang, Xuan; Song, Xin; Ma, Xiaobiao; Hu, Zaoxiu

    2013-10-20

    Pulmonary fibrosis is a common pathological phenomenon in lung cancer patients after chemotherapy or radiotherapy. It is also a key hindrance to the transport of drugs to lung tissue. Peptide transporters have become a target of the rational design of peptides and peptide drugs. The aim of this study is to investigates the expression of peptide transporter 2 (PEPT2) mRNA in the lungs of rats with bleomycin (BLM)-induced pulmonary fibrosis. Fifty healthy adult Sprague-Dawley rats were randomly divided into five groups. One group was untreated (control), the second group was injected with normal saline solution (NS), and the three remaining groups were treated with a single dose of bleomycin to induce pulmonary fibrosis (BLM). Rats from the NS group were killed by exsanguination on day 14. Rats from the BLM group were killed by exsanguination on days 7, 14, and 28. The lung samples were observed under light microscopy and the hydroxyproline concentration was determined. The expression levels of PEPT2 mRNA were measured by RT-PCR. The morphological study showed that collagenous fiber proliferated in the lungs of rats injected with BLM, indicating pulmonary fibrosis. This proliferation was apparent at 14 d post-injection and especially at 28 d post-injection. Hydroxyproline levels increased seven days post-injection compared with the control group and NS group, but there was no significant statistical difference (P>0.05). Hydroxyproline levels significantly increased (Ppulmonary PEPT2 mRNA expression levels among the different groups (P>0.05). PEPT2 is a potential peptide drug target in the treatment of pulmonary fibrosis, although there were no significant changes of PEPT2 mRNA expression in the lungs of rats with bleomycin-induced pulmonary fibrosis.

  11. Progressive APOBEC3B mRNA expression in distant breast cancer metastases.

    Directory of Open Access Journals (Sweden)

    Anieta M Sieuwerts

    Full Text Available APOBEC3B was recently identified as a gain-of-function enzymatic source of mutagenesis, which may offer novel therapeutic options with molecules that specifically target this enzyme. In primary breast cancer, APOBEC3B mRNA is deregulated in a substantial proportion of cases and its expression is associated with poor prognosis. However, its expression in breast cancer metastases, which are the main causes of breast cancer-related death, remained to be elucidated.RNA was isolated from 55 primary breast cancers and paired metastases, including regional lymph node (N = 20 and distant metastases (N = 35. APOBEC3B mRNA levels were measured by RT-qPCR. Expression levels of the primary tumors and corresponding metastases were compared, including subgroup analysis by estrogen receptor (ER/ESR1 status.Overall, APOBEC3B mRNA levels of distant metastases were significantly higher as compared to the corresponding primary breast tumor (P = 0.0015, an effect that was not seen for loco-regional lymph node metastases (P = 0.23. Subgroup analysis by ER-status showed that increased APOBEC3B levels in distant metastases were restricted to metastases arising from ER-positive primary breast cancers (P = 0.002. However, regarding ER-negative primary tumors, only loco-regional lymph node metastases showed increased APOBEC3B expression when compared to the corresponding primary tumor (P = 0.028.APOBEC3B mRNA levels are significantly higher in breast cancer metastases as compared to the corresponding ER-positive primary tumors. This suggests a potential role for APOBEC3B in luminal breast cancer progression, and consequently, a promising role for anti-APOBEC3B therapies in advanced stages of this frequent form of breast cancer.

  12. Mutational analysis ofBRCA1andBRCA2genes in Peruvian families with hereditary breast and ovarian cancer.

    Science.gov (United States)

    Buleje, Jose; Guevara-Fujita, Maria; Acosta, Oscar; Huaman, Francia D P; Danos, Pierina; Murillo, Alexis; Pinto, Joseph A; Araujo, Jhajaira M; Aguilar, Alfredo; Ponce, Jaime; Vigil, Carlos; Castaneda, Carlos; Calderon, Gabriela; Gomez, Henry L; Fujita, Ricardo

    2017-09-01

    Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA1 and BRCA2 germline mutations. We performed a comprehensive analysis of BRCA1 and BRCA2 genes by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. In this series, we found four pathogenic mutations, three previously reported ( BRCA1 : c.302-1G>C and c.815_824dup10; BRCA2 : c.5946delT) and a duplication of adenines in exon 15 in BRCA1 gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. This is the first report to determine the spectrum of mutations in the BRCA1/BRCA2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA1/BRCA2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA1/BRCA2 mutations and a BRCA1 c.4647_4648dupAA as a novel pathogenic mutation.

  13. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Hansen, Thomas V O; Borg, Ake

    2008-01-01

    A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six...

  14. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

    NARCIS (Netherlands)

    B.B.J. Hermsen; R.I. Olivier; R.H.M. Verheijen (René); M. van Beurden (Marc); J.A. de Hullu (Joanne); L.F. Massuger (Leon); C.W. Burger (Curt); C.T. Brekelmans (Cecile); M.J. Mourits; G.H. de Bock (Geertruida); K.N. Gaarenstroom (Katja); H.H. van Boven (Hester); T.M. Mooij (Thea); M.A. Rookus (Matti)

    2007-01-01

    textabstractBRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up

  15. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

    DEFF Research Database (Denmark)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B.

    2017-01-01

    PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigatedfor the first time to our knowledgeassociations of common genetic variants with breast and prostate cancer risks fo...

  16. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

    NARCIS (Netherlands)

    Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Toland, Amanda Ewart; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  17. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, Francois; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Toland, Amanda Ewart; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmana, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Garcia, Encarna B. Gomez; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnes; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Leone, Melanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Zlowocka-Perlowska, Elzbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Paluch, Shani Shimon; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jonson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teule, Alex; Lazaro, Conxi; Brunet, Joan; Angel Pujana, Miquel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomaki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  18. Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Kuchenbaecker, Karoline B; McGuffog, Lesley; Barrowdale, Daniel

    2017-01-01

    mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk...

  19. Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer

    NARCIS (Netherlands)

    Verhoog, L. C.; Brekelmans, C. T.; Seynaeve, C.; Meijers-Heijboer, E. J.; Klijn, J. G.

    2000-01-01

    BRCA1/2 mutation carriers diagnosed with breast cancer have a strongly elevated life-time risk of developing a contralateral tumour. We studied the contralateral breast cancer risk in 164 patients from 83 families with a proven BRCA1 mutation in relation to the age at diagnosis of the first primary

  20. BRCA1 requirement for the fidelity of plasmid DNA double-strand break repair in cultured breast epithelial cells.

    Science.gov (United States)

    Thompson, Eric G; Fares, Hanna; Dixon, Kathleen

    2012-01-01

    The tumor suppressor breast cancer susceptibility protein 1 (BRCA1) protects our cells from genomic instability in part by facilitating the efficient repair of DNA double-strand breaks (DSBs). BRCA1 promotes the error-free repair of DSBs through homologous recombination and is also implicated in the regulation of nonhomologous end joining (NHEJ) repair fidelity. Here, we investigate the role of BRCA1 in NHEJ repair mutagenesis following a DSB. We examined the frequency of microhomology-mediated end joining (MMEJ) and the fidelity of DSB repair relative to BRCA1 protein levels in both control and tumorigenic breast epithelial cells. In addition to altered BRCA1 protein levels, we tested the effects of cellular exposure to mirin, an inhibitor of meiotic recombination enzyme 11 (Mre11) 3'-5'-exonuclease activity. Knockdown or loss of BRCA1 protein resulted in an increased frequency of overall plasmid DNA mutagenesis and MMEJ following a DSB. Inhibition of Mre11-exonuclease activity with mirin significantly decreased the occurrence of MMEJ, but did not considerably affect the overall mutagenic frequency of plasmid DSB repair. The results suggest that BRCA1 protects DNA from mutagenesis during nonhomologous DSB repair in plasmid-based assays. The increased frequency of DSB mutagenesis and MMEJ repair in the absence of BRCA1 suggests a potential mechanism for carcinogenesis. Copyright © 2011 Wiley Periodicals, Inc.

  1. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bolton, Kelly L; Chenevix-Trench, Georgia; Goh, Cindy

    2012-01-01

    Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear....

  2. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

    DEFF Research Database (Denmark)

    Couch, Fergus J; Wang, Xianshu; McGuffog, Lesley

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a fur...

  3. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

    DEFF Research Database (Denmark)

    Lecarpentier, Julie; Silvestri, Valentina; Kuchenbaecker, Karoline B

    2017-01-01

    Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks...

  4. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Friebel, Tara M; Mitra, Nandita

    2016-01-01

    BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA...

  5. Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Friebel, Tara M; Friedman, Eitan

    2018-01-01

    The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with...

  6. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study

    NARCIS (Netherlands)

    Hermsen, B. B. J.; Olivier, R. I.; Verheijen, R. H. M.; van Beurden, M.; de Hullu, J. A.; Massuger, L. F.; Burger, C. W.; Brekelmans, C. T.; Mourits, M. J.; de Bock, G. H.; Gaarenstroom, K. N.; van Boven, H. H.; Mooij, T. M.; Rookus, M. A.

    2007-01-01

    BRCA1/ 2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/ 2 mutation carriers. In this multicentre, observational, follow-up study we

  7. Deleting a Single Protein Restores Critical DNA Repair Process in Mice with Brca1 Gene Mutations | Center for Cancer Research

    Science.gov (United States)

    Women who carry a harmful mutation in the BRCA1 gene have up to an 85 percent greater lifetime risk of developing breast cancer than other women, and up to a 40 percent greater chance of developing ovarian cancer. Thus far, no effective therapies have been developed that overcome the susceptibility to cancer caused by mutations in BRCA1.

  8. Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer : A systematic review

    NARCIS (Netherlands)

    Arts-de Jong, Marieke; de Bock, Geertruida H.; van Asperen, Christi J.; Mourits, Marian J. E.; de Hullu, Joanne A.; Kets, C. Marleen

    The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely,

  9. FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair

    Directory of Open Access Journals (Sweden)

    Zeina Kais

    2016-06-01

    Full Text Available BRCA1/2 proteins function in homologous recombination (HR-mediated DNA repair and cooperate with Fanconi anemia (FA proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.

  10. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk.

    NARCIS (Netherlands)

    Couch, F.J.; Wang, X.; McGuffog, L.; Lee, A.; Olswold, C.; Kuchenbaecker, K.B.; Soucy, P.; Fredericksen, Z.; Barrowdale, D.; Dennis, J.; Gaudet, M.M.; Dicks, E.; Kosel, M.; Healey, S.; Sinilnikova, O.M.; Bacot, F.; Vincent, D.; Hogervorst, F.B.; Peock, S.; Stoppa-Lyonnet, D.; Jakubowska, A.; Radice, P.; Schmutzler, R.K.; Domchek, S.M.; Piedmonte, M.; Singer, C.F.; Friedman, E.; Thomassen, M.; Hansen, T.V.; Neuhausen, S.L.; Szabo, C.I.; Blanco, I.; Greene, M.H.; Karlan, B.Y.; Garber, J.; Phelan, C.M.; Weitzel, J.N.; Montagna, M.; Olah, E.; Andrulis, I.L.; Godwin, A.K.; Yannoukakos, D.; Goldgar, D.E.; Caldes, T.; Nevanlinna, H.; Osorio, A.; Terry, M.B.; Daly, M.B.; Rensburg, E.J. van; Hamann, U.; Ramus, S.J.; Ewart Toland, A.; Caligo, M.A.; Olopade, O.I.; Tung, N.; Claes, K.; Beattie, M.S.; Southey, M.C.; Imyanitov, E.N.; Tischkowitz, M.; Janavicius, R.; John, E.M.; Kwong, A.; Diez, O.; Balmana, J.; Barkardottir, R.B.; Arun, B.K.; Rennert, G.; Teo, S.H.; Ganz, P.A.; Campbell, I.; Hout, A.H. van der; Deurzen, C.H. van; Seynaeve, C.; Gomez Garcia, E.B.; Leeuwen, F.E. van; Meijers-Heijboer, H.E.; Gille, J.J.P.; Ausems, M.G.; Blok, M.J.; Ligtenberg, M.J.L.; Rookus, M.A.; Devilee, P.; Verhoef, S.; Os, T.A. van; Wijnen, J.T.; Frost, D.; Ellis, S.; Fineberg, E.; Platte, R.; Evans, D.G.; Izatt, L.; Eeles, R.A.; Adlard, J.; Eccles, D.M.; Cook, J.; Brewer, C.; Douglas, F.; Hodgson, S.; Morrison, P.J.; Side, L.E.; Donaldson, A.; Houghton, C.; Rogers, M.T.; Dorkins, H.; Eason, J.; Gregory, H.; McCann, E.; Murray, A.; Calender, A.; Hardouin, A.; Berthet, P.; Delnatte, C.; Nogues, C.; Lasset, C.; Houdayer, C.; Leroux, D.; Rouleau, E.; Prieur, F.; Damiola, F.; Sobol, H.; Coupier, I.; Venat-Bouvet, L.; Castera, L.; Gauthier-Villars, M.; Leone, M.; Pujol, P.; Mazoyer, S.; Bignon, Y.J.; Zlowocka-Perlowska, E.; Gronwald, J.; Lubinski, J.; Durda, K.; Jaworska, K.; Huzarski, T.; Spurdle, A.B.; Viel, A.; Peissel, B.; Bonanni, B.; Melloni, G.; Ottini, L.; Papi, L.; Varesco, L.; Tibiletti, M.G.; Peterlongo, P.; Volorio, S.; Manoukian, S.; Pensotti, V.; Arnold, N.; Engel, C.; Deissler, H.; Gadzicki, D.; Gehrig, A.; Kast, K.; Rhiem, K.; Meindl, A.; Niederacher, D.; Ditsch, N.; Plendl, H.; Preisler-Adams, S.; Engert, S.; Sutter, C.; Varon-Mateeva, R.; Wappenschmidt, B.; Weber, B.H.; Arver, B.; Stenmark-Askmalm, M.; Loman, N.; Rosenquist, R.; Einbeigi, Z.; Nathanson, K.L.; Rebbeck, T.R.; Blank, S.V.; Cohn, D.E.; Rodriguez, G.C.; Small, L.; Friedlander, M.; Bae-Jump, V.L.; Fink-Retter, A.; Rappaport, C.; Gschwantler-Kaulich, D.; Pfeiler, G.; Tea, M.K.; Lindor, N.M.; Kaufman, B.; Shimon Paluch, S.; Laitman, Y.; Skytte, A.B.; Gerdes, A.M.; Pedersen, I.S.; Moeller, S.T.; Kruse, T.A.; Jensen, U.B.; Vijai, J.; Sarrel, K.; Robson, M.; Kauff, N.; Mulligan, A.M.; Glendon, G.; Ozcelik, H.; Ejlertsen, B.; Nielsen, F.C.; Jonson, L.; Andersen, M.K.; Ding, Y.C.; Steele, L.; Foretova, L.; Teule, A.; Lazaro, C.; Brunet, J.; Pujana, M.A.; Mai, P.L.; Loud, J.T.; Walsh, C.; Lester, J.; Orsulic, S.; Narod, S.A.; Herzog, J.; Sand, S.R.; Tognazzo, S.; Agata, S.; Vaszko, T.; Weaver, J.; Stavropoulou, A.V.; Buys, S.S.; Romero, A.; Hoya, M. de la; Aittomaki, K.; Muranen, T.A.; Duran, M.; Chung, W.K.; Lasa, A.; Dorfling, C.M.; Miron, A.; Benitez, J.; Senter, L.; Huo, D.; Chan, S.B.; Sokolenko, A.P.; Chiquette, J.; Tihomirova, L.; Friebel, T.M.; Agnarsson, B.A.; Lu, K.H.; Lejbkowicz, F.; James, P.A.; Hall, P.; Dunning, A.M.; Tessier, D.; Cunningham, J.; Slager, S.L.; Wang, C.; Hart, S.; Stevens, K.; Simard, J.; Pastinen, T.; Pankratz, V.S.; Offit, K.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a

  11. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    NARCIS (Netherlands)

    F.J. Couch (Fergus); X. Wang (Xing); L. McGuffog (Lesley); A. Lee; C. Olswold (Curtis); K.B. Kuchenbaecker (Karoline); P. Soucy (Penny); Z. Fredericksen (Zachary); D. Barrowdale (Daniel); J. Dennis (Joe); M.M. Gaudet (Mia); E. Dicks (Ed); M. Kosel (Matthew); S. Healey (Sue); O. Sinilnikova (Olga); F. Bacot (Francois); D. Vincent (Daniel); F.B.L. Hogervorst (Frans); S. Peock (Susan); D. Stoppa-Lyonnet (Dominique); A. Jakubowska (Anna); P. Radice (Paolo); R.K. Schmutzler (Rita); S.M. Domchek (Susan); M. Piedmonte (Marion); C.F. Singer (Christian); E. Friedman (Eitan); M. Thomassen (Mads); T.V.O. Hansen (Thomas); S.L. Neuhausen (Susan); C. Szabo (Csilla); I. Blanco (Ignacio); M.H. Greene (Mark); B. Karlan; J. Garber; C. Phelan (Catherine); J.N. Weitzel (Jeffrey); M. Montagna (Marco); E. Olah; I.L. Andrulis (Irene); A.K. Godwin (Andrew); D. Yannoukakos (Drakoulis); D. Goldgar (David); T. Caldes (Trinidad); H. Nevanlinna (Heli); A. Osorio (Ana); M.-B. Terry (Mary-Beth); M.B. Daly (Mary); E.J. van Rensburg (Elizabeth); U. Hamann (Ute); S.J. Ramus (Susan); A. Ewart-Toland (Amanda); M.A. Caligo (Maria); O.I. Olopade (Olofunmilayo); N. Tung (Nadine); K. Claes (Kathleen); M.S. Beattie (Mary); M.C. Southey (Melissa); E.N. Imyanitov (Evgeny); M. Tischkowitz (Marc); R. Janavicius (Ramunas); E.M. John (Esther); A. Kwong (Ava); O. Diez (Orland); J. Balmana (Judith); R.B. Barkardottir (Rosa); B.K. Arun (Banu); G. Rennert (Gad); S.-H. Teo; P.A. Ganz (Patricia); I. Campbell (Ian); A.H. van der Hout (Annemarie); C.H.M. van Deurzen (Carolien); C.M. Seynaeve (Caroline); E.B. Gómez García (Encarna); F.E. van Leeuwen (F.); H. Meijers-Heijboer (Hanne); J.J. Gille (Johan); M.G.E.M. Ausems (Margreet); M.J. Blok (Marinus); M.J. Ligtenberg (Marjolijn); M.A. Rookus (Matti); P. Devilee (Peter); S. Verhoef; T.A.M. van Os (Theo); J.T. Wijnen (Juul); D. Frost (Debra); S. Ellis (Steve); E. Fineberg (Elena); R. Platte (Radka); D.G. Evans (Gareth); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); D. Eccles (Diana); J. Cook (Jackie); C. Brewer (C.); F. Douglas (Fiona); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); L. Side (Lucy); A. Donaldson (Alan); C. Houghton (Catherine); M.T. Rogers (Mark); H. Dorkins (Huw); J. Eason (Jacqueline); H. Gregory (Helen); E. McCann (Emma); A. Murray (Alexandra); A. Calender (Alain); A. Hardouin (Agnès); P. Berthet (Pascaline); C.D. Delnatte (Capucine); C. Nogues (Catherine); C. Lasset (Christine); C. Houdayer (Claude); D. Leroux (Dominique); E. Rouleau (Etienne); F. Prieur (Fabienne); F. Damiola (Francesca); H. Sobol (Hagay); I. Coupier (Isabelle); L. Vénat-Bouvet (Laurence); L. Castera (Laurent); M. Gauthier-Villars (Marion); M. Léone (Mélanie); P. Pujol (Pascal); S. Mazoyer (Sylvie); Y.-J. Bignon (Yves-Jean); E. Złowocka-Perłowska (Elzbieta); J. Gronwald (Jacek); J. Lubinski (Jan); K. Durda (Katarzyna); K. Jaworska (Katarzyna); T. Huzarski (Tomasz); A.B. Spurdle (Amanda); A. Viel (Alessandra); B. Peissel (Bernard); B. Bonnani (Bernardo); G. Melloni (Giulia); L. Ottini (Laura); L. Papi (Laura); L. Varesco (Liliana); M.G. Tibiletti (Maria Grazia); P. Peterlongo (Paolo); S. Volorio (Sara); S. Manoukian (Siranoush); V. Pensotti (Valeria); N. Arnold (Norbert); C.W. Engel (Christoph); H. Deissler (Helmut); D. Gadzicki (Dorothea); P.A. Gehrig (Paola A.); K. Kast (Karin); K. Rhiem (Kerstin); A. Meindl (Alfons); D. Niederacher (Dieter); N. Ditsch (Nina); H. Plendl (Hansjoerg); S. Preisler-Adams (Sabine); S. Engert (Stefanie); C. Sutter (Christian); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); B.H.F. Weber (Bernhard); B. Arver (Brita Wasteson); M. Stenmark-Askmalm (M.); N. Loman (Niklas); R. Rosenquist (R.); Z. Einbeigi (Zakaria); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); S.V. Blank (Stephanie); D.E. Cohn (David); G.C. Rodriguez (Gustavo); L. Small (Laurie); M. Friedlander (Michael); V.L. Bae-Jump (Victoria L.); A. Fink-Retter (Anneliese); C. Rappaport (Christine); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); M.-K. Tea; N.M. Lindor (Noralane); B. Kaufman (Bella); S. Shimon Paluch (Shani); Y. Laitman (Yael); A.-B. Skytte (Anne-Bine); A-M. Gerdes (Anne-Marie); I.S. Pedersen (Inge Sokilde); S.T. Moeller (Sanne Traasdahl); T.A. Kruse (Torben); U.B. Jensen; J. Vijai (Joseph); K. Sarrel (Kara); M. Robson (Mark); N. Kauff (Noah); A.M. Mulligan (Anna Marie); G. Glendon (Gord); H. Ozcelik (Hilmi); B. Ejlertsen (Bent); F.C. Nielsen (Finn); L. Jønson (Lars); M.K. Andersen (Mette); Y.C. Ding (Yuan); L. Steele (Linda); L. Foretova (Lenka); A. Teulé (A.); C. Lazaro (Conxi); J. Brunet (Joan); M.A. Pujana (Miguel); P.L. Mai (Phuong); J.T. Loud (Jennifer); C.S. Walsh (Christine); K.J. Lester (Kathryn); S. Orsulic (Sandra); S. Narod (Steven); J. Herzog (Josef); S.R. Sand (Sharon); S. Tognazzo (Silvia); S. Agata (Simona); T. Vaszko (Tibor); J. Weaver (JoEllen); A. Stavropoulou (Alexandra); S.S. Buys (Saundra); A. Romero (Alfonso); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); T.A. Muranen (Taru); M. Duran; W.K. Chung (Wendy); A. Lasa (Adriana); C.M. Dorfling (Cecelia); A. Miron (Alexander); J. Benítez (Javier); L. Senter (Leigha); D. Huo (Dezheng); S. Chan (Salina); A. Sokolenko (Anna); J. Chiquette (Jocelyne); L. Tihomirova (Laima); M.O.W. Friebel (Mark ); B.A. Agnarsson (Bjarni); K.H. Lu (Karen); F. Lejbkowicz (Flavio); P.A. James (Paul ); A.S. Hall (Alistair); A.M. Dunning (Alison); Y. Tessier (Yann); J. Cunningham (Jane); S. Slager (Susan); C. Wang (Chen); S. Hart (Stewart); K. Stevens (Kristen); J. Simard (Jacques); T. Pastinen (Tomi); V.S. Pankratz (Shane); K. Offit (Kenneth); D.F. Easton (Douglas); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); H. Thorne (Heather); E. Niedermayr (Eveline); Å. Borg (Åke); H. Olsson; H. Jernström (H.); K. Henriksson (Karin); K. Harbst (Katja); M. Soller (Maria); U. Kristoffersson (Ulf); A. Öfverholm (Anna); M. Nordling (Margareta); P. Karlsson (Per); A. von Wachenfeldt (Anna); A. Liljegren (Annelie); A. Lindblom (Annika); G.B. Bustinza; J. Rantala (Johanna); B. Melin (Beatrice); C.E. Ardnor (Christina Edwinsdotter); M. Emanuelsson (Monica); H. Ehrencrona (Hans); M.H. Pigg (Maritta ); S. Liedgren (Sigrun); M.A. Rookus (M.); S. Verhoef (S.); F.E. van Leeuwen (F.); M.K. Schmidt (Marjanka); J.L. de Lange (J.); J.M. Collee (Margriet); A.M.W. van den Ouweland (Ans); M.J. Hooning (Maartje); C.J. van Asperen (Christi); J.T. Wijnen (Juul); R.A.E.M. Tollenaar (Rob); P. Devilee (Peter); T.C.T.E.F. van Cronenburg; C.M. Kets; A.R. Mensenkamp (Arjen); R.B. van der Luijt (Rob); C.M. Aalfs (Cora); T.A.M. van Os (Theo); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); E.B. Gomez Garcia (Encarna); J.C. Oosterwijk (Jan); M.J. Mourits; G.H. de Bock (Geertruida); S.D. Ellis (Steve); E. Fineberg (Elena); Z. Miedzybrodzka (Zosia); L. Jeffers (Lisa); T.J. Cole (Trevor); K.-R. Ong (Kai-Ren); J. Hoffman (Jonathan); M. James (Margaret); J. Paterson (Joan); A. Taylor (Amy); A. Murray (Anna); M.J. Kennedy (John); D.E. Barton (David); M.E. Porteous (Mary); S. Drummond (Sarah); C. Brewer (Carole); E. Kivuva (Emma); A. Searle (Anne); S. Goodman (Selina); R. Davidson (Rosemarie); V. Murday (Victoria); N. Bradshaw (Nicola); L. Snadden (Lesley); M. Longmuir (Mark); C. Watt (Catherine); S. Gibson (Sarah); E. Haque (Eshika); E. Tobias (Ed); A. Duncan (Alexis); L. Izatt (Louise); C. Jacobs (Chris); C. Langman (Caroline); A.F. Brady (Angela); S.A. Melville (Scott); K. Randhawa (Kashmir); J. Barwell (Julian); G. Serra-Feliu (Gemma); I.O. Ellis (Ian); F. Lalloo (Fiona); J. Taylor (James); A. Male (Alison); C. Berlin (Cheryl); R. Collier (Rebecca); F. Douglas (Fiona); O. Claber (Oonagh); I. Jobson (Irene); L.J. Walker (Lisa); D. McLeod (Diane); D. Halliday (Dorothy); S. Durell (Sarah); B. Stayner (Barbara); S. Shanley (Susan); N. Rahman (Nazneen); R. Houlston (Richard); A. Stormorken (Astrid); E. Bancroft (Elizabeth); E. Page (Elizabeth); A. Ardern-Jones (Audrey); K. Kohut (Kelly); J. Wiggins (Jennifer); E. Castro (Elena); S.R. Killick; S. Martin (Sue); D. Rea (Dan); A. Kulkarni (Anjana); O. Quarrell (Oliver); C. Bardsley (Cathryn); S. Goff (Sheila); G. Brice (Glen); L. Winchester (Lizzie); C. Eddy (Charlotte); V. Tripathi (Vishakha); V. Attard (Virginia); A. Lehmann (Anna); A. Lucassen (Anneke); G. Crawford (Gabe); D. McBride (Donna); S. Smalley (Sarah); S. Mazoyer (Sylvie); F. Damiola (Francesca); L. Barjhoux (Laure); C. Verny-Pierre (Carole); S. Giraud (Sophie); D. Stoppa-Lyonnet (Dominique); B. Buecher (Bruno); V. Moncoutier (Virginie); M. Belotti (Muriel); C. Tirapo (Carole); A. de Pauw (Antoine); B. Bressac-de Paillerets (Brigitte); O. Caron (Olivier); Y.-J. Bignon (Yves-Jean); N. Uhrhammer (Nancy); V. Bonadona (Valérie); S. Handallou (Sandrine); A. hardouin (Agnès); H. Sobol (Hagay); V. Bourdon (Violaine); T. Noguchi (Tetsuro); A. Remenieras (Audrey); F. Eisinger (François); J.-P. Peyrat; J. Fournier (Joëlle); F. Révillion (Françoise); P. Vennin (Philippe); C. Adenis (Claude); R. Lidereau (Rosette); L. Demange (Liliane); D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); E. Barouk-Simonet (Emmanuelle); F. Bonnet (Françoise); V. Bubien (Virginie); N. Sevenet (Nicolas); M. Longy (Michel); C. Toulas (Christine); R. Guimbaud (Rosine); L. Gladieff (Laurence); V. Feillel (Viviane); H. Dreyfus (Hélène); C. Rebischung (Christine); M. Peysselon (Magalie); F. Coron (Fanny); L. Faivre (Laurence); M. Lebrun (Marine); C. Kientz (Caroline); S.F. Ferrer; M. Frenay (Marc); I. Mortemousque (Isabelle); F. Coulet (Florence); C. Colas (Chrystelle); F. Soubrier; J. Sokolowska (Johanna); M. Bronner (Myriam); H. Lynch (Henry); C.L. Snyder (Carrie); M. Angelakos (Maggie); J. Maskiell (Judi); G.S. Dite (Gillian)

    2013-01-01

    textabstractBRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer),

  12. JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks

    DEFF Research Database (Denmark)

    Watanabe, Sugiko; Watanabe, Kenji; Akimov, Vyacheslav

    2013-01-01

    Chromatin ubiquitylation flanking DNA double-strand breaks (DSBs), mediated by RNF8 and RNF168 ubiquitin ligases, orchestrates a two-branch pathway, recruiting repair factors 53BP1 or the RAP80-BRCA1 complex. We report that human demethylase JMJD1C regulates the RAP80-BRCA1 branch of this DNA...

  13. Expression of connexin 43 mRNA and protein in developing follicles of prepubertal porcine ovaries

    Science.gov (United States)

    Melton, C.M.; Zaunbrecher, G.M.; Yoshizaki, G.; Patio, R.; Whisnant, S.; Rendon, A.; Lee, V.H.

    2001-01-01

    A major form of cell-cell communication is mediated by gap junctions, aggregations of intercellular channels composed of connexins (Cxs), which are responsible for exchange of low molecular weight (family of related proteins. This study was designed to determine the ontogeny of connexin 43 (Cx43) during early stages of follicular development in prepubertal porcine ovaries. A partial-length (412 base) cDNA clone was obtained from mature porcine ovaries and determined to have 98% identity with published porcine Cx43. Northern blot analysis demonstrated a 4.3-kb mRNA in total RNA isolated from prepubertal and adult porcine ovaries. In-situ hybridization revealed that Cx43 mRNA was detectable in granulosa cells of primary follicles but undetectable in dormant primordial follicles. The intensity of the signal increased with follicular growth and was greatest in the large antral follicles. Immunohistochemical evaluation indicated that Cx43 protein expression correlated with the presence of Cx43 mRNA. These results indicate that substantial amounts of Cx43 are first expressed in granulosa cells following activation of follicular development and that this expression increases throughout follicular growth and maturation. These findings suggest an association between the enhancement of intercellular gap-junctional communication and onset of follicular growth. ?? 2001 Elsevier Science Inc. All rights reserved.

  14. Increased mRNA expression of cytochrome oxidase in dorsal raphe nucleus of depressive suicide victims

    Science.gov (United States)

    Sanchez-Bahillo, A; Bautista-Hernandez, V; Barcia Gonzalez, Carlos; Bañon, R; Luna, A; Hirsch, EC; Herrero, Maria-Trinidad

    2008-01-01

    Suicidal behavior is a problem with important social repercussions. Some groups of the population show a higher risk of suicide; for example, depression, alcoholism, psychosis or drug abuse frequently precedes suicidal behavior. However, the relationship between metabolic alterations in the brain and premorbid clinical symptoms of suicide remains uncertain. The serotonergic and noradrenergic systems have frequently been, implicated in suicidal behavior and the amount of serotonin in the brain and CSF of suicide victims has been found to be low compared with normal subjects. However, there are contradictory results regarding the role of noradrenergic neurons in the mediation of suicide attempts, possibly reflecting the heterogeneity of conditions that lead to a common outcome. In the present work we focus on the subgroup of suicide victims that share a common diagnosis of major depression. Based on post-mortem studies analyzing mRNA expression by in situ hybridization, serotonergic neurons from the dorsal raphe nucleus (DRN) from depressive suicide victims are seen to over-express cytochrome oxidase mRNA. However, no corresponding changes were found in the expression of tyrosine hydroxylase (TH) mRNA in the noradrenergic neurons of the Locus Coeruleus (LC). These results suggest that, despite of the low levels of serotonin described in suicide victims, the activity of DRN neurons could increase in the suicidally depressed, probably due to the over activation of serotonin re-uptake. No alteration was found in noradrenergic neurons, suggesting that they play no crucial role in the suicidal behavior of depressive patients. PMID:18728743

  15. Basal keratin expression in breast cancer by quantification of mRNA and by immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Pluciennik Elzbieta

    2010-04-01

    Full Text Available Abstract Definitions of basal-like breast cancer phenotype vary, and microarray-based expression profiling analysis remains the gold standard for the identification of these tumors. Immunohistochemical identification of basal-like carcinomas is hindered with a fact, that on microarray level not all of them express basal-type cytokeratin 5/6, 14 and 17. We compared expression of cytokeratin 5, 14 and 17 in 115 patients with operable breast cancer estimated by real-time RT-PCR and immunohistochemistry. Despite the method of dichotomization and statistical analysis, there were cases with discordant results comparing immunohistochemistry and RT-PCR analysis. For dichotomisation based on quartiles and ROC, 14% of cases were negative on immunohistochemical examination for CK5/6, but presented high CK5 mRNA levels. There were also 48-55% cases, which were CK5/6-immunopositive, but were negative by mRNA examination. Similar discordances were observed for CK14 and CK17. Basal keratin mRNAs did not correlate with ER mRNA levels, while immunohistochemistry produced significant relationship with ER status. Our observation suggest that both method may produce different results in a small proportion of cases. Discordance between immunohistochemistry and RT-PCR may confound attempts to establish a simple methods for identification of basal-like tumors.

  16. Changes in the responsiveness of hypothalamic prokineticin 2 mRNA expression to food deprivation in developing female rats.

    Science.gov (United States)

    Iwasa, Takeshi; Matsuzaki, Toshiya; Munkhzaya, Munkhsaikhan; Tungalagsuvd, Altankhuu; Kawami, Takako; Murakami, Masahiro; Yamasaki, Mikio; Kato, Takeshi; Kuwahara, Akira; Yasui, Toshiyuki; Irahara, Minoru

    2014-05-01

    Prokineticin 2 (PK2) is highly expressed in several regions of the central nervous system, including the hypothalamus. Recently, it has been suggested that PK2 plays a role in appetite regulation. In adult male rodents, the administration of PK2 decreased food intake, and PK2 mRNA expression was reduced by food deprivation. Usually, the changes in the expression levels of appetite-regulating factors induced in response to fasting are not fully established during the neonatal period. Thus, we investigated the developmental changes in hypothalamic PK2 mRNA expression and the alterations in hypothalamic PK2 mRNA expression induced by fasting during the pre-pubertal period in female rats. The changes in hypothalamic neuropeptide Y (NPY) mRNA expression were also examined because NPY is a potent appetite regulatory factor. Hypothalamic PK2 mRNA expression was extremely high during the early neonatal period (postnatal day (PND) 5) compared with that observed during subsequent periods (PND15, 25, and 42), while hypothalamic NPY mRNA expression did not differ among any of the examined periods. A fasting-induced reduction in hypothalamic PK2 mRNA expression was observed on PND5, but no fasting-induced increase in hypothalamic NPY mRNA expression was seen during the same period. In addition, the fasting-induced reduction in hypothalamic PK2 mRNA expression observed on PND5 was more marked than that seen on PND25. These results suggest that the sensitivity of hypothalamic PK2 expression to undernutrition develops during the early neonatal period, when the responses of other appetite regulatory factors to such pressures remain immature. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

  17. Checkpoint Functions of the BRCA1/BARD1 Tumor Suppressor

    National Research Council Canada - National Science Library

    Modi, Ami

    2007-01-01

    .... To study the function of mitotic BARD1 phosphorylation, I used an siRNA-mediated approach to knockdown endogenous BARD1 expression and then restore expression with siRNA-resistant exogenous forms of BARD1...

  18. Investigation of Exportin 5 (XPO5 mRNA expression in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Samira Shakerizadeh

    2017-01-01

    Full Text Available Background and objectives: Deregulation in the expression of microRNAs is involved in the pathogenesis of various malignancies. Impaired microRNAs processing pathway is one possible mechanism for global deregulation of the miRNAs. Exportin 5 (XPO5 is a key member of this pathway that links nuclear and cytoplasmic steps of miRNAs biogenesis together. XPO5 deregulation has been reported in some cancers but very little is known about its role in breast cancer. Therefore, this study aimed to evaluate the mRNA expression of XPO5 in breast cancer in an Iranian population. Methods: In this case-control study, 30 tumoral tissues and 30 tumor-free margins were collected from breast cancer patients. After RNA extraction and cDNA synthesis, XPO5 mRNA expression level was assessed using quantitative Real-Time PCR. Results: Our results showed that XPO5 was overexpressed in 53.3% of tumoral tissues but the difference in the gene expression level between tumoral tissues and tumor-free margins was not statistically significant (P-value=0.834. XPO5 expression level showed no statistically significant correlation and association with clinical and pathological parameters. Conclusion: Overexpression of XPO5 in large percent of patients indicates that high level of XPO5 expression may be a tumorigenic factor for breast cancer which needs to be investigated more deeply.

  19. Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy.

    Science.gov (United States)

    Ames, E G; Lawson, M J; Mackey, A J; Holmes, J W

    2013-09-01

    Cardiac hypertrophy has been well-characterized at the level of transcription. During cardiac hypertrophy, genes normally expressed primarily during fetal heart development are re-expressed, and this fetal gene program is believed to be a critical component of the hypertrophic process. Recently, alternative splicing of mRNA transcripts has been shown to be temporally regulated during heart development, leading us to consider whether fetal patterns of splicing also reappear during hypertrophy. We hypothesized that patterns of alternative splicing occurring during heart development are recapitulated during cardiac hypertrophy. Here we present a study of isoform expression during pressure-overload cardiac hypertrophy induced by 10 days of transverse aortic constriction (TAC) in rats and in developing fetal rat hearts compared to sham-operated adult rat hearts, using high-throughput sequencing of poly(A) tail mRNA. We find a striking degree of overlap between the isoforms expressed differentially in fetal and pressure-overloaded hearts compared to control: forty-four percent of the isoforms with significantly altered expression in TAC hearts are also expressed at significantly different levels in fetal hearts compared to control (Phypertrophy and fetal heart development are significantly enriched for genes involved in cytoskeletal organization, RNA processing, developmental processes, and metabolic enzymes. Our data strongly support the concept that mRNA splicing patterns normally associated with heart development recur as part of the hypertrophic response to pressure overload. These findings suggest that cardiac hypertrophy shares post-transcriptional as well as transcriptional regulatory mechanisms with fetal heart development. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue

    DEFF Research Database (Denmark)

    Petersen, Annabeth Høgh; Jørgensen, Mads Malik Aagaard; Nielsen, Henriette Roed

    2016-01-01

    mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild......1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE......Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder...

  1. Quantitation of the mRNA expression of the epidermal growth factor system

    DEFF Research Database (Denmark)

    Sørensen, B S; Tørring, N; Bor, M V

    2000-01-01

    The epidermal growth factor (EGF) system is a rapidly expanding system of growth factors involved in many aspects of normal and cancerous growth. We have developed a method for the quantitation of mRNA coding for all six growth factors activating the human EGF receptor (HER-1) and for the quantit......The epidermal growth factor (EGF) system is a rapidly expanding system of growth factors involved in many aspects of normal and cancerous growth. We have developed a method for the quantitation of mRNA coding for all six growth factors activating the human EGF receptor (HER-1......) and for the quantitation of mRNA for the receptors HER-1 and its preferred dimerization partner, HER-2. The method is based on the generation of specific RNA standards, which are amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) with the sample RNA and a set of calibrators. The resulting calibration...... stromal cells in primary culture express EGF, heparin-binding EGF (HB-EGF), amphiregulin, betacellulin, and epiregulin as well as the HER-1 and HER-2 receptors, whereas no transforming growth factor-alpha mRNA is found. Furthermore, activation of the EGF system in these cells by stimulation with HB...

  2. Body weight and risk of breast cancer in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Manders, P.; Pijpe, A.; Hooning, M.J.; Kluijt, I; Vasen, H.F.A.; Hoogerbrugge, N.; van Asperen, C.J.; Meijers-Heijboer, E.J.; Ausems, M.G.E.M.; van Os, T.A.M.; Gomez-Garcia, E.B.; Brohet, R.M.; van Leeuwen, F.E.; Rookus, M.A.

    2011-01-01

    Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a

  3. Body weight and risk of breast cancer in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Manders, Peggy; Pijpe, Anouk; Hooning, Maartje J.; Kluijt, Irma; Vasen, Hans F. A.; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne; Ausems, Margreet G. E. M.; van Os, Theo A.; Gomez-Garcia, Encarna B.; Brohet, Richard M.; van Leeuwen, Flora E.; Rookus, Matti A.

    Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a

  4. Morphological predictors of BRCA1 germline mutations in young women with breast cancer

    NARCIS (Netherlands)

    Southey, M. C.; Ramus, S. J.; Dowty, J. G.; Smith, L. D.; Tesoriero, A. A.; Wong, E. E. M.; Dite, G. S.; Jenkins, M. A.; Byrnes, G. B.; Winship, I.; Phillips, K-A; Giles, G. G.; Hopper, J. L.

    2011-01-01

    BACKGROUND: Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.

  5. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I. M.; Hoogerbrugge, N.; Blickman, J. G.; Boetes, C.

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control

  6. Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer.

    Science.gov (United States)

    Torres-Mejía, Gabriela; Royer, Robert; Llacuachaqui, Marcia; Akbari, Mohammad R; Giuliano, Anna R; Martínez-Matsushita, Louis; Angeles-Llerenas, Angélica; Ortega-Olvera, Carolina; Ziv, Elad; Lazcano-Ponce, Eduardo; Phelan, Catherine M; Narod, Steven A

    2015-03-01

    Germline mutations in the BRCA1 and BRCA2 genes confer an estimated 58% to 80% lifetime risk of breast cancer. In general, screening is done for cancer patients if a relative has been diagnosed with breast or ovarian cancer. There are few data on the prevalence of mutations in these genes in Mexican women with breast cancer and this hampers efforts to develop screening policies in Mexico. We screened 810 unselected women with breast cancer from three cities in Mexico (Mexico City, Veracruz, and Monterrey) for mutations in BRCA1 and BRCA2, including a panel of 26 previously reported mutations. Thirty-five mutations were identified in 34 women (4.3% of total) including 20 BRCA1 mutations and 15 BRCA2 mutations. Twenty-two of the 35 mutations were recurrent mutations (62.8%). Only five of the 34 mutation carriers had a first-degree relative with breast cancer (three with BRCA1 and two with BRCA2 mutations). These results support the rationale for a strategy of screening for recurrent mutations in all women with breast cancer in Mexico, as opposed to restricting screening to those with a sister or mother with breast or ovarian cancer. These results will impact cancer genetic testing in Mexico and the identification of at-risk individuals who will benefit from increased surveillance. Cancer Epidemiol Biomarkers Prev; 24(3); 498-505. ©2014 AACR. ©2014 American Association for Cancer Research.

  7. Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

    Science.gov (United States)

    Moon, D H; Lee, J-M; Noonan, A M; Annunziata, C M; Minasian, L; Houston, N; Hays, J L; Kohn, E C

    2013-01-01

    Background: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). Methods: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. Results: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (Pcarboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6–65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. Conclusion: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs. PMID:23867999

  8. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    K.-A. Phillips (Kelly-Anne); R.L. Milne (Roger); M.A. Rookus (Matti); M.J. Daly (Mark); A.C. Antoniou (Antonis C.); S. Peock (Susan); D. Frost (Debra); D.F. Easton (Douglas); S.D. Ellis (Steve); M. Friedlander (Michael); S.S. Buys (Saundra); N. Andrieu (Nadine); C. Nogues (Catherine); D. Stoppa-Lyonnet (Dominique); V. Bonadona (Valérie); P. Pujol (Pascal); S.-A. McLachlan (Sue-Anne); E.M. John (Esther); M.J. Hooning (Maartje); C.M. Seynaeve (Caroline); R.A.E.M. Tollenaar (Rob); D. Goldgar (David); M.B. Terry (Mary Beth); T. Caldes (Trinidad); P.C. Weideman (Prue C.); I.L. Andrulis (Irene); C.F. Singer (Christian); K. Birch (Kate); J. Simard (Jacques); M.C. Southey (Melissa); H.L. Olsson (Håkan L.); A. Jakubowska (Anna); E. Olah; A-M. Gerdes (Anne-Marie); L. Foretova (Lenka); J.L. Hopper (John)

    2013-01-01

    textabstractPurpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up

  9. BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome

    Directory of Open Access Journals (Sweden)

    Ingrid Petroni Ewald

    2016-06-01

    Full Text Available Abstract Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4% individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.

  10. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility

    NARCIS (Netherlands)

    de Jong, MM; Nolte, IM; Meerman, GJT; van der Graaf, WTA; Oosterwijk, JC; Kleibeuker, JH; Schaapveld, M; de Vries, EGE

    This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer

  11. Risk-reducing mastectomy in BRCA1/2 mutation carriers : Factors influencing uptake and timing

    NARCIS (Netherlands)

    van Driel, Catheleine M.; Eltahir, Yassir; de Vries, J; Jaspers, Jan P.; Oosterwijk, Jan C.; Mourits, Marian J.; de Bock, Geertruida H.

    INTRODUCTION: Strategies in case of high risk of breast cancer in BRCA1/2 mutation carriers are either intensive breast cancer screening or risk-reducing mastectomy (RRM). Both options have a high physical and psychosexual impact. The aim of this study is to investigate who chooses when to undergo

  12. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Kuchenbaecker, Karoline B; Hopper, John L; Barnes, Daniel R

    2017-01-01

    Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer hi...

  13. Over-representation of two specific haplotypes among chromosomes harbouring BRCA1 mutations.

    Science.gov (United States)

    Osorio, Ana; de la Hoya, Miguel; Rodríguez-López, Raquel; Granizo, Juan José; Díez, Orland; Vega, Ana; Durán, Mercedes; Carracedo, Angel; Baiget, Montserrat; Caldés, Trinidad; Benítez, Javier

    2003-06-01

    The BRCA1 gene is included in a 200-400 kb region that is subjected to a recombination suppression mechanism; this region shows nearly complete linkage disequilibrium for a series of common biallelic polymorphisms, all of them with rarer allele frequency close to 0.4. These series of SNPs define two major haplotypes designated as class I and class II. In the present study, we have determined haplotype classes in the index case of 106 breast/ovarian cancer families previously screened for mutations in the BRCA genes and we have found that haplotype II (the less frequent in the control population) is over-represented among chromosomes harbouring mutations in BRCA1. In addition, we have defined a subtype of chromosomes characterized by haplotype I and one specific allele for the microsatellite marker D17S855, which are also more frequently associated with BRCA1 mutations. These findings may have important consequences for the selection of families with higher probabilities of carrying mutations in the BRCA1 gene.

  14. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

    DEFF Research Database (Denmark)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco

    2012-01-01

    Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortiu...

  15. High frequency of BRCA1/2 and p53 somatic inactivation in sporadic ...

    Indian Academy of Sciences (India)

    Introduction. Our knowledge about the role of BRCA genes in hereditary breast and ovarian cancer is rapidly expanding (Zikan et al. 2005). However, we know very little about their role in spo- radic breast ovarian cancer. In epithelial ovarian cancer, al- lelic losses of the BRCA1 gene are found in 23%-44% and of BRCA2 in ...

  16. Psychological impact of receiving a BRCA1/BRCA2 test result

    NARCIS (Netherlands)

    Lodder, L.; Frets, P. G.; Trijsburg, R. W.; Meijers-Heijboer, E. J.; Klijn, J. G.; Duivenvoorden, H. J.; Tibben, A.; Wagner, A.; van der Meer, C. A.; van den Ouweland, A. M.; Niermeijer, M. F.

    2001-01-01

    Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and

  17. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele fre...

  18. BRCA1 and BRCA2 gene mutations in breast cancer among west ...

    African Journals Online (AJOL)

    Our review was able to establish that very few studies have described the mutations of the BRCA1 / 2 genes in Africa. The dearth of scientific data in West Africa has impacted negatively on prevention, sensitization and management of breast cancer. We strongly suggest studies in general cancer registries of these countries ...

  19. A Macrohistone Variant Links Dynamic Chromatin Compaction to BRCA1-Dependent Genome Maintenance

    Directory of Open Access Journals (Sweden)

    Simran Khurana

    2014-08-01

    Full Text Available Appropriate DNA double-strand break (DSB repair factor choice is essential for ensuring accurate repair outcome and genomic integrity. The factors that regulate this process remain poorly understood. Here, we identify two repressive chromatin components, the macrohistone variant macroH2A1 and the H3K9 methyltransferase and tumor suppressor PRDM2, which together direct the choice between the antagonistic DSB repair mediators BRCA1 and 53BP1. The macroH2A1/PRDM2 module mediates an unexpected shift from accessible to condensed chromatin that requires the ataxia telangiectasia mutated (ATM-dependent accumulation of both proteins at DSBs in order to promote DSB-flanking H3K9 dimethylation. Remarkably, loss of macroH2A1 or PRDM2, as well as experimentally induced chromatin decondensation, impairs the retention of BRCA1, but not 53BP1, at DSBs. As a result, macroH2A1 and/or PRDM2 depletion causes epistatic defects in DSB end resection, homology-directed repair, and the resistance to poly(ADP-ribose polymerase (PARP inhibition—all hallmarks of BRCA1-deficient tumors. Together, these findings identify dynamic, DSB-associated chromatin reorganization as a critical modulator of BRCA1-dependent genome maintenance.

  20. Functional characterization of BRCA1 gene variants by mini-gene splicing assay

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Dandanell, Mette; Jønson, Lars

    2014-01-01

    are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13 BRCA1 variants...... of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213-1G>A, c.670+1delG, c.4185+1G>A, and c.5075-1G......>C), whereas six BRCA1 variants were classified as neutral (c.-19-22_-19-21dupAT, c.302-15C>G, c.547+14delG, c.4676-20A>G, c.4987-21G>T, and c.5278-14C>G) and one BRCA1 variant remained unclassified (c.670+16G>A). In conclusion, our study emphasizes that in silico analysis and mini-gene splicing assays...

  1. Dihydroorotate dehydrogenase mRNA and protein expression analysis in normal and drug-resistant cells.

    Science.gov (United States)

    Löffler, M; Klein, A; Hayek-Ouassini, M; Knecht, W; Konrad, L

    2004-10-01

    To follow the expression of the fourth enzyme of pyrimidine de novo synthesis dihydroorotate dehydrogenase (DHODH) in cells and tissues, we studied the DHODH mRNA expression by means of RT-PCR in rat tissues. Rabbit polyclonal anti-DHODH immunoglobulins were applied for immunochemical quantification of the enzyme protein by Western blotting. In mouse B-lymphocytes, which were adapted to tolerate up to a 50-fold concentration of the DHODH inhibitor leflunomide, a 20 fold protein overexpression was measured. Southern blotting indicated DHODH gene amplification.

  2. Keratinocyte growth factor mRNA expression in periodontal ligament fibroblasts

    DEFF Research Database (Denmark)

    Dabelsteen, S; Wandall, H H; Grøn, B

    1997-01-01

    Keratinocyte growth factor (KGF) is a fibroblast growth factor which mediates epithelial growth and differentiation. KGF is expressed in subepithelial fibroblasts, but generally not in fibroblasts of deep connective tissue, such as fascia and ligaments. Here we demonstrate that KGF mRNA is expres......Keratinocyte growth factor (KGF) is a fibroblast growth factor which mediates epithelial growth and differentiation. KGF is expressed in subepithelial fibroblasts, but generally not in fibroblasts of deep connective tissue, such as fascia and ligaments. Here we demonstrate that KGF m...

  3. Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico

    Science.gov (United States)

    Villarreal-Garza, Cynthia; Alvarez-Gómez, Rosa María; Pérez-Plasencia, Carlos; Herrera, Luis A.; Herzog, Josef; Castillo, Danielle; Mohar, Alejandro; Castro, Clementina; Gallardo, Lenny N.; Gallardo, Dolores; Santibáñez, Miguel; Blazer, Kathleen R.; Weitzel, Jeffrey N.

    2014-01-01

    Background Frequent recurrent BRCA1 and BRCA2 gene (BRCA) mutations among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 ex9-12del), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economical screening for hereditary breast and ovarian cancer in Mexico. Methods In a multistage approach, 188 cancer cases unselected for family cancer history (92 ovarian cancer and 96 breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL®) of 115 recurrent mutations in a multiplex assay (114 on a mass spectroscopy platform, and a PCR assay for the BRCA1 ex9-12del mutation), followed by sequencing of all BRCA exons and adjacent intronic regions, and BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL negative cases. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. Results BRCA mutations were detected in 28% (26/92) of ovarian cancer cases and 15% (14/96) of breast cancer cases overall and 27% (9/33) of triple negative breast cancer. Most breast cancer cases were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of the BRCA-associated ovarian cancer cases and 29% of the BRCA-associated breast cancer cases. At 2% of the sequencing and MLPA cost, the HISPANEL detected 68% of all BRCA mutations. Conclusion In this study, we found a remarkably high prevalence of BRCA mutations among ovarian and breast cases not selected for family history, and BRCA1 ex9-12del explained one third of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer

  4. Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations.

    Science.gov (United States)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Izarzugaza, Jose M G; Eklund, Aron C; Li, Yang; Liu, Joyce; Szallasi, Zoltan; Matulonis, Ursula A; Richardson, Andrea L; Iglehart, J Dirk; Wang, Zhigang C

    2013-01-01

    Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative

  5. [Expressions of RASSF1A, Galectin-3 and TPO mRNA in papillary thyroid carcinoma and their clinical significance].

    Science.gov (United States)

    Xu, Mei-rong; Chen, Yun; Zhou, Shao-rong; Chi, Ming-ming; Chen, Sen-lin; Liu, Lei-yu

    2009-05-01

    To investigate the mRNA expressions of RASSF1A, Galectin-3 and TPO in papillary thyroid carcinoma and some other thyroid benign lesions, and evaluate their diagnostic significance. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of RASSF1A, galectin-3 and TPO in the samples from 73 cases, including 23 cases with papillary thyroid cancer, 16 with nodular goiter, 29 with thyroid adenoma and 5 with Hashimoto's disease. A statistically significant difference in the mRNA expression of RASSF1A, Galectin-3 and TPO was observed between papillary thyroid carcinoma and follicular benign lesions (P0.05). A negative correlation of the expression of RASSF1A and Galectin-3 mRNA was found between thyroid benign lesions and malignant ones (P = 0.000). While the mRNA expression of RASSF1A and TPO was positively correlated between benign and malignant lesions (P = 0.028). Loss of expression of RASSF1A and TPO mRNA but high expression of Galectin-3 mRNA in papillary thyroid carcinoma are common. Therefore, the products of these three genes may be closely related to the development of thyroid papillary carcinoma, and may be used as useful markers in differential diagnosis of papillary thyroid carcinoma from the benign lesions. The results are more reliable if this detection method is used in combination with other techniques.

  6. HemaExplorer: a database of mRNA expression profiles in normal and malignant haematopoiesis

    DEFF Research Database (Denmark)

    Bagger, Frederik Otzen; Rapin, Nicolas; Theilgaard-Mönch, Kim

    2013-01-01

    The HemaExplorer (http://servers.binf.ku.dk/hemaexplorer) is a curated database of processed mRNA Gene expression profiles (GEPs) that provides an easy display of gene expression in haematopoietic cells. HemaExplorer contains GEPs derived from mouse/human haematopoietic stem and progenitor cells...... as well as from more differentiated cell types. Moreover, data from distinct subtypes of human acute myeloid leukemia is included in the database allowing researchers to directly compare gene expression of leukemic cells with those of their closest normal counterpart. Normalization and batch correction...... lead to full integrity of the data in the database. The HemaExplorer has comprehensive visualization interface that can make it useful as a daily tool for biologists and cancer researchers to assess the expression patterns of genes encountered in research or literature. HemaExplorer is relevant for all...

  7. Induction of Ski protein expression upon luteinization in rat granulosa cells without a change in its mRNA expression.

    Science.gov (United States)

    Kim, Hyun; Yamanouchi, Keitaro; Matsuwaki, Takashi; Nishihara, Masugi

    2012-01-01

    The Ski protein is implicated in the proliferation/differentiation of a variety of cells. We previously reported that the Ski protein is present in granulosa cells of atretic follicles, but not in preovulatory follicles, suggesting that Ski has a role in apoptosis of granulosa cells. However, granulosa cells cannot only undergo apoptosis but can alternatively differentiate into luteal cells. It is unknown whether Ski is expressed and has a role in granulosa cells undergoing luteinization. Thus, the aim of the present study was to determine the localization of the Ski protein in the rat ovary during luteinization to examine if Ski might play a role in this process. In order to examine the Ski protein expression during the progression of luteinization, follicular growth was induced in immature female rats by administration of equine chorionic gonadotropin, and luteinization was induced by human chorionic gonadotropin treatment to mimic the luteinizing hormone (LH) surge. While no Ski-positive granulosa cells were present in the preovulatory follicle, Ski protein expression was induced in response to the LH surge and was maintained after formation of the corpus luteum (CL). Although the Ski protein is absent from the granulosa cells of the preovulatory follicle, its mRNA (c-ski) was expressed, and the level of c-ski mRNA was unchanged even after the LH surge. The combined results demonstrated that Ski protein expression is induced in granulosa cells upon luteinization, and suggested that its expression is regulated posttranscriptionally.

  8. Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Karthik V. Giridhar

    2017-11-01

    Full Text Available The Memorial Sloan Kettering Cancer Center (MSKCC prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR of 0.14, p < 0.0001, 95% confidence interval (CI 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34 were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001. Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

  9. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts.

    Science.gov (United States)

    Vousooghi, Nasim; Zarei, Seyed Zeinolabedin; Sadat-Shirazi, Mitra-Sadat; Eghbali, Fatemeh; Zarrindast, Mohammad Reza

    2015-10-01

    Excessive playing of computer games like some other behaviors could lead to addiction. Addictive behaviors may induce their reinforcing effects through stimulation of the brain dopaminergic mesolimbic pathway. The status of dopamine receptors in the brain may be parallel to their homologous receptors in peripheral blood lymphocytes (PBLs). Here, we have investigated the mRNA expression of dopamine D3, D4 and D5 receptors in PBLs of computer game addicts (n = 20) in comparison to normal subjects (n = 20), using a real-time PCR method. The results showed that the expression level of D3 and D4 dopamine receptors in computer game addicts were not statistically different from the control group. However, the expression of the mRNA of D5 dopamine receptor was significantly down-regulated in PBLs of computer game addicts and reached 0.42 the amount of the control group. It is concluded that unlike with drug addiction, the expression levels of the D3 and D4 dopamine receptors in computer game addicts are not altered compared to the control group. However, reduced level of the D5 dopamine receptor in computer game addicts may serve as a peripheral marker in studies where the confounding effects of abused drugs are unwanted.

  10. Downregulation of TIM-3 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus

    Energy Technology Data Exchange (ETDEWEB)

    Cai, X.Z. [Central Laboratory, First Affiliated Hospital, China Medical University, Shenyang (China); Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang (China); Huang, W.Y.; Qiao, Y.; Chen, Y.; Du, S.Y.; Chen, D.; Yu, S. [Central Laboratory, First Affiliated Hospital, China Medical University, Shenyang (China); Liu, N. [Department of Nephrology, First Affiliated Hospital, China Medical University, Shenyang (China); Dou, L.Y. [Central Laboratory, First Affiliated Hospital, China Medical University, Shenyang (China); Jiang, Y. [Central Laboratory, First Affiliated Hospital, China Medical University, Shenyang (China); Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang (China); Department of Dermatology, First Affiliated Hospital, China Medical University, Shenyang (China)

    2014-10-17

    The T-cell immunoglobulin and mucin domain (TIM) family is associated with autoimmune diseases, but its expression level in the immune cells of systemic lupus erythematosus (SLE) patients is not known. The aim of this study was to investigate whether the expression of TIM-3 mRNA is associated with pathogenesis of SLE. Quantitative real-time reverse transcription-polymerase chain reaction analysis (qRT-PCR) was used to determine TIM-1, TIM-3, and TIM-4 mRNA expression in peripheral blood mononuclear cells (PBMCs) from 132 patients with SLE and 62 healthy controls. The PBMC surface protein expression of TIMs in PBMCs from 20 SLE patients and 15 healthy controls was assayed by flow cytometry. Only TIM-3 mRNA expression decreased significantly in SLE patients compared with healthy controls (P<0.001). No significant differences in TIM family protein expression were observed in leukocytes from SLE patients and healthy controls (P>0.05). SLE patients with lupus nephritis (LN) had a significantly lower expression of TIM-3 mRNA than those without LN (P=0.001). There was no significant difference in the expression of TIM-3 mRNA within different classes of LN (P>0.05). Correlation of TIM-3 mRNA expression with serum IgA was highly significant (r=0.425, P=0.004), but was weakly correlated with total serum protein (r{sub s}=0.283, P=0.049) and serum albumin (r{sub s}=0.297, P=0.047). TIM-3 mRNA expression was weakly correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; r{sub s}=-0.272, P=0.032). Our results suggest that below-normal expression of TIM-3 mRNA in PBMC may be involved in the pathogenesis of SLE.

  11. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2.

    Science.gov (United States)

    Lakhani, Sunil R; Van De Vijver, Marc J; Jacquemier, Jocelyne; Anderson, Thomas J; Osin, Peter P; McGuffog, Lesley; Easton, Douglas F

    2002-05-01

    The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined.

  12. Regulation of DNA methyltransferase 1 transcription in BRCA1-mutated breast cancer: a novel crosstalk between E2F1 motif hypermethylation and loss of histone H3 lysine 9 acetylation.

    Science.gov (United States)

    Li, Da; Bi, Fang-Fang; Cao, Ji-Min; Cao, Chen; Liu, Bo; Yang, Qing

    2014-02-06

    DNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating DNMT1 expression remains largely unknown. Epigenetic regulation of DNMT1 was assessed in 85 invasive ductal carcinomas from BRCA1 mutation carriers. Association between clinicopathological features and DNMT1 promoter methylation was determined using Fisher's exact test. Univariate analysis of survival was performed using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to identify the independent prognostic factors for overall survival. Hypermethylated E2F transcription factor 1 (E2F1) motif is a key regulatory element for the DNMT1 gene in BRCA1-mutated breast cancer. Mechanistically, the abnormal E2F1 motif methylation-mediated loss of active histone H3 lysine 9 acetylation (H3K9ac) and transcription factor E2F1 enrichment synergistically inhibited the transcription of DNMT1. Clinicopathological data indicated that the hypermethylated E2F1 motif was associated with histological grade, lymph node, Ki67 and E-cadherin status; univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients. Our findings imply that genetic (such as BRCA1 mutation) and epigenetic mechanisms (such as DNA methylation, histone modification, transcription factor binding) are jointly involved in the malignant progression of DNMT1-related breast cancer.

  13. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development

    Science.gov (United States)

    Nair, Sreejith J.; Zhang, Xiaowen; Chiang, Huai-Chin; Jahid, Md Jamiul; Wang, Yao; Garza, Paula; April, Craig; Salathia, Neeraj; Banerjee, Tapahsama; Alenazi, Fahad S.; Ruan, Jianhua; Fan, Jian-Bing; Parvin, Jeffrey D.; Jin, Victor X.; Hu, Yanfen; Li, Rong

    2016-01-01

    The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout are largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restores developmental transcription at puberty, alters luminal epithelial homoeostasis, yet remains deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription programme during mammary gland development. PMID:26941120

  14. IL-1β directly suppress ghrelin mRNA expression in ghrelin-producing cells.

    Science.gov (United States)

    Bando, Mika; Iwakura, Hiroshi; Ueda, Yoko; Ariyasu, Hiroyuki; Inaba, Hidefumi; Furukawa, Yasushi; Furuta, Hiroto; Nishi, Masahiro; Akamizu, Takashi

    2017-05-15

    In animal models, ghrelin production is suppressed by LPS administration. To elucidate the detailed molecular mechanisms involved in the phenomenon, we investigated the effects of LPS and LPS-inducible cytokines, including TNF-α, IL-1β, and IL-6, on the expression of ghrelin in the ghrelin-producing cell line MGN3-1. These cells expressed IL-1R, and IL-1β significantly suppressed ghrelin mRNA levels. The suppressive effects of IL-1β were attenuated by knockdown of IKKβ, suggesting the involvement of the NF-κB pathway. These results suggested that IL-1β is a major regulator of ghrelin expression during inflammatory processes. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data

    Directory of Open Access Journals (Sweden)

    Bussemaker Harmen J

    2004-03-01

    Full Text Available Abstract Background Functional genomics studies are yielding information about regulatory processes in the cell at an unprecedented scale. In the yeast S. cerevisiae, DNA microarrays have not only been used to measure the mRNA abundance for all genes under a variety of conditions but also to determine the occupancy of all promoter regions by a large number of transcription factors. The challenge is to extract useful information about the global regulatory network from these data. Results We present MA-Networker, an algorithm that combines microarray data for mRNA expression and transcription factor occupancy to define the regulatory network of the cell. Multivariate regression analysis is used to infer the activity of each transcription factor, and the correlation across different conditions between this activity and the mRNA expression of a gene is interpreted as regulatory coupling strength. Applying our method to S. cerevisiae, we find that, on average, 58% of the genes whose promoter region is bound by a transcription factor are true regulatory targets. These results are validated by an analysis of enrichment for functional annotation, response for transcription factor deletion, and over-representation of cis-regulatory motifs. We are able to assign directionality to transcription factors that control divergently transcribed genes sharing the same promoter region. Finally, we identify an intrinsic limitation of transcription factor deletion experiments related to the combinatorial nature of transcriptional control, to which our approach provides an alternative. Conclusion Our reliable classification of ChIP positives into functional and non-functional TF targets based on their expression pattern across a wide range of conditions provides a starting point for identifying the unknown sequence features in non-coding DNA that directly or indirectly determine the context dependence of transcription factor action. Complete analysis results are

  16. Expression of PEPT2 mRNA in Lung Tissue of Rats with Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Li LI

    2013-10-01

    Full Text Available Background and objective Pulmonary fibrosis is a common pathological phenomenon in lung cancer patients after chemotherapy or radiotherapy. It is also a key hindrance to the transport of drugs to lung tissue. Peptide transporters have become a target of the rational design of peptides and peptide drugs. The aim of this study is to investigates the expression of peptide transporter 2 (PEPT2 mRNA in the lungs of rats with bleomycin (BLM-induced pulmonary fibrosis. Methods Fifty healthy adult Sprague-Dawley rats were randomly divided into five groups. One group was untreated (control, the second group was injected with normal saline solution (NS, and the three remaining groups were treated with a single dose of bleomycin to induce pulmonary fibrosis (BLM. Rats from the NS group were killed by exsanguination on day 14. Rats from the BLM group were killed by exsanguination on days 7, 14, and 28. The lung samples were observed under light microscopy and the hydroxyproline concentration was determined. The expression levels of PEPT2 mRNA were measured by RT-PCR. Results The morphological study showed that collagenous fiber proliferated in the lungs of rats injected with BLM, indicating pulmonary fibrosis. This proliferation was apparent at 14 d post-injection and especially at 28 d post-injection. Hydroxyproline levels increased seven days post-injection compared with the control group and NS group, but there was no significant statistical difference (P>0.05. Hydroxyproline levels significantly increased (P0.05. Conclusion PEPT2 is a potential peptide drug target in the treatment of pulmonary fibrosis, although there were no significant changes of PEPT2 mRNA expression in the lungs of rats with bleomycin-induced pulmonary fibrosis.

  17. Characterization and mRNA expression analysis of a novel ARG1 splicing mutation causing hyperargininemia.

    Science.gov (United States)

    Villegas-Ruiz, Vanessa; Campos-Garcia, Felix J; Contreras-Capetillo, Silvina; Moreno-Graciano, Claudia M; Maldonado-Solis, Felipe A; Maldonado-Solis, Mario A; Zenteno, Juan C

    2015-12-01

    Biallelic mutations in the ARG1 gene result in an uncommon autosomal recessive inborn defect of the urea cycle known as hyperargininemia (OMIM #207800). ARG1 splicing mutations are not reported often, and they are probably related to a more severe phenotype than missense mutations. In this article, we describe the results of molecular studies in a young hyperargininemia patient carrying a novel splicing mutation in ARG1. Molecular analyses included PCR amplification and direct nucleotide sequencing of the ARG1 gene. RT-PCR analysis was performed to investigate the effect of the mutation in mRNA splicing and in the expression of ARG1 isoforms. Mutational analysis identified a novel homozygous ARG1 IVS4-1G>C point mutation in the patient's DNA. Blood leukocyte mRNA was analyzed to demonstrate the splicing defect caused by this mutation. Sequencing of ARG1 RT-PCR products allowed the characterization of a mutated transcript retaining 51-bp from intron 4. In addition, two new, alternatively spliced ARG1 transcripts lacking either exon 4 or exons 4 and 5 were identified in mRNA from the patient and from controls. Our results expand the mutational spectrum in hyperargininemia patients and indicate that the novel splicing mutation results in an aberrant transcript retaining intronic sequences. Two novel alternatively spliced ARG1 transcripts were also recognized. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  18. On a stochastic gene expression with pre-mRNA, mRNA and protein contribution.

    Science.gov (United States)

    Rudnicki, Ryszard; Tomski, Andrzej

    2015-12-21

    In this paper we develop a model of stochastic gene expression, which is an extension of the model investigated in the paper [T. Lipniacki, P. Paszek, A. Marciniak-Czochra, A.R. Brasier, M. Kimmel, Transcriptional stochasticity in gene expression, J. Theor. Biol. 238 (2006) 348-367]. In our model, stochastic effects still originate from random fluctuations in gene activity status, but we precede mRNA production by the formation of pre-mRNA, which enriches classical transcription phase. We obtain a stochastically regulated system of ordinary differential equations (ODEs) describing evolution of pre-mRNA, mRNA and protein levels. We perform mathematical analysis of a long-time behavior of this stochastic process, identified as a piece-wise deterministic Markov process (PDMP). We check exact results using numerical simulations for the distributions of all three types of particles. Moreover, we investigate the deterministic (adiabatic) limit state of the process, when depending on parameters it can exhibit two specific types of behavior: bistability and the existence of the limit cycle. The latter one is not present when only two kinds of gene expression products are considered. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    van den Broek, Alexandra J; van 't Veer, Laura J; Hooning, Maartje J; Cornelissen, Sten; Broeks, Annegien; Rutgers, Emiel J; Smit, Vincent T H B M; Cornelisse, Cees J; van Beek, Mike; Janssen-Heijnen, Maryska L; Seynaeve, Caroline; Westenend, Pieter J; Jobsen, Jan J; Siesling, Sabine; Tollenaar, Rob A E M; van Leeuwen, Flora E; Schmidt, Marjanka K

    2016-02-10

    To determine prospectively overall and age-specific estimates of contralateral breast cancer (CBC) risk for young patients with breast cancer with or without BRCA1/2 mutations. A cohort of 6,294 patients with invasive breast cancer diagnosed under 50 years of age and treated between 1970 and 2003 in 10 Dutch centers was tested for the most prevalent BRCA1/2 mutations. We report absolute risks and hazard ratios within the cohort from competing risk analyses. After a median follow-up of 12.5 years, 578 CBCs were observed in our study population. CBC risk for BRCA1 and BRCA2 mutation carriers was two to three times higher than for noncarriers (hazard ratios, 3.31 [95% CI, 2.41 to 4.55; P Age at diagnosis of the first breast cancer was a significant predictor of CBC risk in BRCA1/2 mutation carriers only; those diagnosed before age 41 years had a 10-year cumulative CBC risk of 23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age (P = .02); our review of published studies showed ranges of 24% to 31% before age 40 years (BRCA1: 24% to 32%; BRCA2:17% to 29%) and 8% to 21% after 40 years (BRCA1: 11% to 52%; BRCA2: 7% to 18%), respectively. Age at first breast cancer is a strong risk factor for cumulative CBC risk in BRCA1/2 mutation carriers. Considering the available evidence, age-specific risk estimates should be included in counseling. © 2015 by American Society of Clinical Oncology.

  20. Association between basal-like phenotype andBRCA1/2germline mutations in Korean breast cancer patients.

    Science.gov (United States)

    Jung, J; Kang, E; Gwak, J M; Seo, A N; Park, S Y; Lee, A S; Baek, H; Chae, S; Kim, E K; Kim, S W

    2016-10-01

    BRCA mutation testing allows index patients and their families to be provided with appropriate cancer risk-reduction strategies. Because of the low prevalence of BRCA mutations in unselected breast cancer patients and the high cost of genetic testing, it is important to identify the subset of women who are likely to carry BRCA mutations. In the present study, we examined the association between BRCA1 / 2 germline mutations and the immunohistochemical features of breast cancer. In a retrospective review of 498 breast cancer patients who had undergone BRCA testing at Seoul National University Bundang Hospital between July 2003 and September 2012, we gathered immunohistochemical information on estrogen receptor (er), progesterone receptor (pr), her2 (human epidermal growth factor receptor 2), cytokeratin 5/6, egfr (epidermal growth factor receptor), and p53 status. Among the 411 patients eligible for the study, 50 (12.2%) had germline mutations in BRCA1 or BRCA2 . Of the 93 patients with triple-negative breast cancer (tnbc), 25 with BRCA1 / 2 mutations were identified ( BRCA1, 20.4%; BRCA2, 6.5%). On univariate analysis, er, pr, cytokeratin 5/6, egfr, and tnbc were found to be related to BRCA1 mutations, but on multivariate analysis, only tnbc was significantly associated with BRCA1 mutations. Among patients with early-onset breast cancer or with a family history of breast or ovarian cancer, BRCA1 mutations were significantly more prevalent in the tnbc group than in the non-tnbc group. In the present study, tnbc was the only independent predictor of BRCA1 mutation in patients at high risk of hereditary breast and ovarian cancers. Other histologic features of basal-like breast cancer did not improve the estimate of BRCA1 mutation risk.

  1. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christopher A Maxwell

    2011-11-01

    Full Text Available Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((wHR = 1.09 (95% CI 1.02-1.16, p(trend = 0.017; and n = 3,965, (wHR = 1.04 (95% CI 0.94-1.16, p(trend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

  2. Fasting and exercise differentially regulate BDNF mRNA expression in human skeletal muscle.

    Science.gov (United States)

    Walsh, Jeremy J; Edgett, Brittany A; Tschakovsky, Michael E; Gurd, Brendon J

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) gene expression was measured in human skeletal muscle following 3 intensities of exercise and a 48-h fast. No change in BDNF mRNA was observed following exercise, while fasting upregulated BDNF by ∼ 3.5-fold. These changes were dissociated from changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following exercise (+2- to 15-fold) and fasting (∼-25%). These results challenge our understanding of the response of BDNF to energetic stress and highlight the importance of future work in this area.

  3. Tumor-associated antigens identified by mRNA expression profiling as tumor rejection epitopes

    DEFF Research Database (Denmark)

    Andersen, Marie Louise; Ruhwald, Morten; Thorn, Mette

    2003-01-01

    Thirteen H-2b-binding peptides derived from six potentially overexpressed proteins in p53-/- thymoma (SM7) cells were studied for immunogenecity and vaccine-induced prevention of tumor growth in mice inoculated with SM7 tumor cells. Six of the peptides generated specific CTL responses after immun...... derived from potentially overexpressed tumor proteins, as identified by mRNA expression profiling of p53-/- thymoma cells, at best results in a weak tumor protection thus questioning this way of detection of new tumor rejection epitopes....

  4. Ustilago maydis natural antisense transcript expression alters mRNA stability and pathogenesis.

    Science.gov (United States)

    Donaldson, Michael E; Saville, Barry J

    2013-07-01

    Ustilago maydis infection of Zea mays leads to the production of thick-walled diploid teliospores that are the dispersal agent for this pathogen. Transcriptome analyses of this model biotrophic basidiomycete fungus identified natural antisense transcripts (NATs) complementary to 247 open reading frames. The U. maydis NAT cDNAs were fully sequenced and annotated. Strand-specific RT-PCR screens confirmed expression and identified NATs preferentially expressed in the teliospore. Targeted screens revealed four U. maydis NATs that are conserved in a related fungus. Expression of NATs in haploid cells, where they are not naturally occurring, resulted in increased steady-state levels of some complementary mRNAs. The expression of one NAT, as-um02151, in haploid cells resulted in a twofold increase in complementary mRNA levels, the formation of sense-antisense double-stranded RNAs, and unchanged Um02151 protein levels. This led to a model for NAT function in the maintenance and expression of stored teliospore mRNAs. In testing this model by deletion of the regulatory region, it was determined that alteration in NAT expression resulted in decreased pathogenesis in both cob and seedling infections. This annotation and functional analysis supports multiple roles for U. maydis NATs in controlling gene expression and influencing pathogenesis. © 2013 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

  5. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y

    2011-01-01

    and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1...

  6. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples

    Directory of Open Access Journals (Sweden)

    Sin Hang Lee

    2016-02-01

    Full Text Available Three sets of polymerase chain reaction (PCR primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  7. The Expression of Antibiotic Resistance Methyltransferase Correlates with mRNA Stability Independently of Ribosome Stalling.

    Science.gov (United States)

    Dzyubak, Ekaterina; Yap, M N

    2016-12-01

    Members of the Erm methyltransferase family modify 23S rRNA of the bacterial ribosome and render cross-resistance to macrolides and multiple distantly related antibiotics. Previous studies have shown that the expression of erm is activated when a macrolide-bound ribosome stalls the translation of the leader peptide preceding the cotranscribed erm Ribosome stalling is thought to destabilize the inhibitory stem-loop mRNA structure and exposes the erm Shine-Dalgarno (SD) sequence for translational initiation. Paradoxically, mutations that abolish ribosome stalling are routinely found in hyper-resistant clinical isolates; however, the significance of the stalling-dead leader sequence is largely unknown. Here, we show that nonsense mutations in the Staphylococcus aureus ErmB leader peptide (ErmBL) lead to high basal and induced expression of downstream ErmB in the absence or presence of macrolide concomitantly with elevated ribosome methylation and resistance. The overexpression of ErmB is associated with the reduced turnover of the ermBL-ermB transcript, and the macrolide appears to mitigate mRNA cleavage at a site immediately downstream of the ermBL SD sequence. The stabilizing effect of antibiotics on mRNA is not limited to ermBL-ermB; cationic antibiotics representing a ribosome-stalling inducer and a noninducer increase the half-life of specific transcripts. These data unveil a new layer of ermB regulation and imply that ErmBL translation or ribosome stalling serves as a "tuner" to suppress aberrant production of ErmB because methylated ribosome may impose a fitness cost on the bacterium as a result of misregulated translation. Copyright © 2016 Dzyubak and Yap.

  8. mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate Cancer

    Science.gov (United States)

    Penney, Kathryn L.; Sinnott, Jennifer A.; Fall, Katja; Pawitan, Yudi; Hoshida, Yujin; Kraft, Peter; Stark, Jennifer R.; Fiorentino, Michelangelo; Perner, Sven; Finn, Stephen; Calza, Stefano; Flavin, Richard; Freedman, Matthew L.; Setlur, Sunita; Sesso, Howard D.; Andersson, Swen-Olof; Martin, Neil; Kantoff, Philip W.; Johansson, Jan-Erik; Adami, Hans-Olov; Rubin, Mark A.; Loda, Massimo; Golub, Todd R.; Andrén, Ove; Stampfer, Meir J.; Mucci, Lorelei A.

    2011-01-01

    Purpose Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. PMID:21537050

  9. Peroxisome Proliferator-Activated Receptors Alpha, Beta, and Gamma mRNA and Protein Expression in Human Fetal Tissues

    Directory of Open Access Journals (Sweden)

    Barbara D. Abbott

    2010-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study examines expression of PPAR, , and mRNA and protein in human fetal tissues. With increasing fetal age, mRNA expression of PPAR and increased in liver, but PPAR decreased in heart and intestine, and PPAR decreased in adrenal. Adult and fetal mean expression of PPAR, , and mRNA did not differ in intestine, but expression was lower in fetal stomach and heart. PPAR and mRNA in kidney and spleen, and PPAR mRNA in lung and adrenal were lower in fetal versus adult. PPAR in liver and PPAR mRNA in thymus were higher in fetal versus adult. PPAR protein increased with fetal age in intestine and decreased in lung, kidney, and adrenal. PPAR protein in adrenal and PPAR in kidney decreased with fetal age. This study provides new information on expression of PPAR subtypes during human development and will be important in evaluating the potential for the developing human to respond to PPAR environmental or pharmaceutical agonists.

  10. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria

    2013-01-01

    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA...... repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous...... ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated...

  11. Microelectronic DNA assay for the detection of BRCA1 gene mutations

    Science.gov (United States)

    Chen, Hua; Han, Jie; Li, Jun; Meyyappan, Meyya

    2004-01-01

    Mutations in BRCA1 are characterized by predisposition to breast cancer, ovarian cancer and prostate cancer as well as colon cancer. Prognosis for this cancer survival depends upon the stage at which cancer is diagnosed. Reliable and rapid mutation detection is crucial for the early diagnosis and treatment. We developed an electronic assay for the detection of a representative single nucleotide polymorphism (SNP), deletion and insertion in BRCA1 gene by the microelectronics microarray instrumentation. The assay is rapid, and it takes 30 minutes for the immobilization of target DNA samples, hybridization, washing and readout. The assay is multiplexing since it is carried out at the same temperature and buffer conditions for each step. The assay is also highly specific, as the signal-to-noise ratio is much larger than recommended value (72.86 to 321.05 vs. 5) for homozygotes genotyping, and signal ratio close to the perfect value 1 for heterozygotes genotyping (1.04).

  12. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins.

    Science.gov (United States)

    Prakash, Rohit; Zhang, Yu; Feng, Weiran; Jasin, Maria

    2015-04-01

    Homologous recombination (HR) is a major pathway for the repair of DNA double-strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  13. Increased leptin mRNA expression in the blood of dogs naturally infected by Leishmania infantum.

    Science.gov (United States)

    Di Loria, Antonio; Squillacioti, Caterina; De Luca, Adriana; Veneziano, Vincenzo; Mirabella, Nicola; Guccione, Jacopo; Santoro, Domenico

    2014-12-01

    Canine leishmaniosis (CL) is a severe and potentially fatal zoonosis caused by the protozoan Leishmania infantum. Severe forms of CL are commonly associated with a non-protective, humoral immune-response and high parasitic loads. Leptin, a 16 kD hormone mainly secreted by adipocytes, regulates both the innate and adaptive immunity. The goal of this study was to evaluate leptin mRNA expression levels in blood samples from privately owned dogs with CL (n = 11) and healthy controls (n = 10) using quantitative, real-time polymerase chain reaction. Blood samples from dogs with CL expressed significantly higher leptin mRNA levels (two-fold) compared to healthy controls (P = 0.018). The results suggest a possible involvement of leptin in the pathophysiology of Leishmania infection in dogs and the possible use of leptin as a biomarker for CL. Future studies investigating the immunological role of leptin in dogs with CL are warranted. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. cWords - systematic microRNA regulatory motif discovery from mRNA expression data

    DEFF Research Database (Denmark)

    Rasmussen, Simon Horskjær; Jacobsen, Anders; Krogh, Anders

    2013-01-01

    -transcriptional regulation by small RNAs is mediated through partial complementary binding to messenger RNAs leaving nucleotide signatures or motifs throughout the entire transcriptome. Computational methods for discovery and analysis of sequence motifs in high-throughput mRNA expression profiling experiments are becoming......BACKGROUND:Post-transcriptional regulation of gene expression by small RNAs and RNA binding proteins is of fundamental importance in development of complex organisms, and dysregulation of regulatory RNAs can influence onset, progression and potentially be target for treatment of many diseases. Post...... clustering and visualization that accompany the cWords analysis for more intuitive and effective data interpretation. To demonstrate the versatility of cWords we show that it can also be used for identification of potential siRNA off-target binding. Moreover, cWords analysis of an experiment profiling mRNAs...

  15. Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers.

    Science.gov (United States)

    Pataky, Reka; Armstrong, Linlea; Chia, Stephen; Coldman, Andrew J; Kim-Sing, Charmaine; McGillivray, Barbara; Scott, Jenna; Wilson, Christine M; Peacock, Stuart

    2013-07-10

    Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting. We constructed a Markov model of annual MRI and mammography screening for BRCA1/2 carriers, using local data and published values. We calculated cost-effectiveness as cost per quality-adjusted life-year gained (QALY), and conducted one-way and probabilistic sensitivity analysis. The incremental cost-effectiveness ratio (ICER) of annual mammography plus MRI screening, compared to annual mammography alone, was $50,900/QALY. After incorporating parameter uncertainty, MRI screening is expected to be a cost-effective option 86% of the time at a willingness-to-pay of $100,000/QALY, and 53% of the time at a willingness-to-pay of $50,000/QALY. The model is highly sensitive to the cost of MRI; as the cost is increased from $200 to $700 per scan, the ICER ranges from $37,100/QALY to $133,000/QALY. The cost-effectiveness of using MRI and mammography in combination to screen for breast cancer in BRCA1/2 mutation carriers is finely balanced. The sensitivity of the results to the cost of the MRI screen itself warrants consideration: in jurisdictions with higher MRI costs, screening may not be a cost-effective use of resources, but improving the efficiency of MRI screening will also improve cost-effectiveness.

  16. Determine the Impact of Novel BRCA1 Translation Start Sites on Therapy Resistance in Ovarian Cancer

    Science.gov (United States)

    2016-07-01

    sequence and structural features resulted in a preference for Met-297 as the translation initiation site. DNA damage–induced alternative protein... nuclear export. J Biol Chem. 2002;277(24):21315–21324. 51. Sobhian B, et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Sci...cisplatin, DNA damage, homologous recombination 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18. NUMBER 19a. NAME OF RESPONSIBLE PERSON OF ABSTRACT

  17. A New Cell-Free System to Study BRCA1 Function

    Science.gov (United States)

    2016-06-01

    One interpretation is that fork convergence triggers a conformational change in CMG that makes it responsive to the action of BRCA1-BARD1, which is...approach (cell-free egg extracts) to interrogate genome maintenance processes and underwent rigorous training in the design and interpretation of...Protein Research in Copenhagen , Denmark. Thomas Graham will start a post-doctoral position in the laboratory of Vanessa Ruta at Rockefeller

  18. Prevalence of the most frequent BRCA1 mutations in Polish population.

    Science.gov (United States)

    Brozek, Izabela; Cybulska, Celina; Ratajska, Magdalena; Piatkowska, Magdalena; Kluska, Anna; Balabas, Aneta; Dabrowska, Michalina; Nowakowska, Dorota; Niwinska, Anna; Pamula-Pilat, Jolanta; Tecza, Karolina; Pekala, Wioletta; Rembowska, Jolanta; Nowicka, Karina; Mosor, Maria; Januszkiewicz-Lewandowska, Danuta; Rachtan, Jadwiga; Grzybowska, Ewa; Nowak, Jerzy; Steffen, Jan; Limon, Janusz

    2011-08-01

    The purpose of our study was to establish the frequency and distribution of the four most common BRCA1 mutations in Polish general population and in a series of breast cancer patients. Analysis of the population frequency of 5382insC (c.5266dupC), 300T >G (p.181T >G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5) mutations of the BRCA1 gene were performed on a group of respectively 16,849, 13,462, 12,485 and 3923 anonymous samples collected at birth in seven Polish provinces. The patient group consisted of 1845 consecutive female breast cancer cases. The most frequent BRCA1 mutation in the general population was 5382insC found in 29 out of 16,849 samples (0.17%). 300T >G and 3819del5 mutations were found in respectively 11 of 13,462 (0.08%) and four of 3923 (0.1%) samples. The population prevalence for combined Polish founder 5382insC and 300T >G mutations was 0.25% (1/400). The frequencies of 5382insC and 300T >G carriers among consecutive breast cancer cases were, respectively, 1.9% (35/1845) and 1.2% (18/1486). Comparing these data with the population frequency, we calculated the relative risk of breast cancer for 5382insC mutation at OR = 17 and for 300T >G mutation at OR = 26. Our results, based on large population studies, show high frequencies of founder 5382insC and 300T >G BRCA1 mutations in Polish general population. Carriage of one of these mutations is connected with a very high relative risk of breast cancer.

  19. Novel mechanisms of PARP inhibitor resistance in BRCA1 deficient cancers

    Science.gov (United States)

    2016-08-01

    essential for error-free repair of DNA double strand breaks via homologous recombination (HR) (Gudmundsdottir & Ashworth, 2006), while PARPs are...integrated plasmid reporter, DR-GFP, is cut with the rare cutter, I-SceI nuclease, resulting in a double strand break. When this break is repaired via...another cell line, BR5, a BRCA1-deficient mouse ovarian cancer cell line which is exceptionally sensitive to PARPi treatment (Figure 17C). Though BR5

  20. BRCA1 Protein Complexes: Dynamic Changes and Functions Important in Breast Cancer

    Science.gov (United States)

    2007-04-01

    associated with loss of tumor suppression activity. The currently identified substrates include histone proteins, p53, Fanconi anemia protein D2, and...Hospital, 5415 Boulevard de l’Assomption, Montreal, QC, Canada H1T 2M4. ‡To whom correspondence should be addressed at: Department of Pathology...region were essential in the complex milieu of the nucleus. These results link the BRCA1- de - pendent ubiquitination of the polymerase with DNA damage

  1. Regulation of BRCA1 Function by DNA Damage-Induced Site-Specific Phosphorylation

    Science.gov (United States)

    2007-06-01

    concentration of Mg 2. Interestingly, mammalian cell extracts deficient in Fanconi anemia proteins had a 3–9-fold reduction in DNA end-joining...Mavinakere, M., and Campbell, C. Deficient DNA end joining activity in extracts from fanconi anemia fibroblasts. J. Biol. Chem., 276: 9543–9549...suppressive properties of BRCA1 de - rive, at least in part, from its response to tissue-specific DNA damage. In this regard, certain oxidative

  2. Understanding missense mutations in the BRCA1 gene: An evolutionary approach

    OpenAIRE

    Fleming, Melissa A.; Potter, John D.; Ramirez, Christina J.; Ostrander, Gary K.; Ostrander, Elaine A.

    2003-01-01

    The role of missense changes in BRCA1 in breast cancer susceptibility has been difficult to establish. We used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11 and missense changes likely to disrupt gene function, aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation. We used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under pos...

  3.  Poly(ADP-ribose polymerase (PARP inhibitors in BRCA1/2 cancer therapy

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2012-06-01

    Full Text Available  A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose polymerases (PARP. PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers.

  4. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes.

    Science.gov (United States)

    Akbari, Mohammad R; Zhang, Shiyu; Fan, Isabel; Royer, Robert; Li, Song; Risch, Harvey; McLaughlin, John; Rosen, Barry; Sun, Ping; Narod, Steven A

    2011-11-01

    Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, pcancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.

  5. Health behaviors among Ashkenazi Jewish individuals receiving counseling for BRCA1 and BRCA2 mutations.

    Science.gov (United States)

    Quach, Jackie; Porter, Kyle; Leventhal, Howard; Kelly, Kimberly M

    2009-01-01

    Little of the research involving individuals undergoing testing for BRCA1/2 mutations has examined the effect of genetic counseling and testing on diet, exercise, and vitamin use. This study examined diet, exercise, and vitamin use among 120 Ashkenazi Jewish individuals with a personal and/or family history of breast and/or ovarian cancer who presented for BRCA1/2 genetic counseling and testing. Health behaviors were measured at pre-counseling and 6 months post-results. T-tests or ANOVAs were used to test for association of health behaviors with potential predictors: personal cancer history, anxiety, perceived cancer risk, gene status, and perceived efficacy of health behaviors. Multivariable linear regression analysis found gender (P = .007) and perceived efficacy of a healthy diet (P = .005) to be significantly associated with healthy food consumption; gender (P = .003), education (P = .01), and personal cancer history (P = .02) were significantly associated with unhealthy food consumption; higher age (P < .001) and perceived efficacy (P < .001) were significantly associated with higher vitamin use. Paired t-tests found no significant changes in diet, vitamin use, and exercise as a result of genetic counseling and testing. We conclude that genetic counseling and testing had little impact on health behaviors. Rather, perceived efficacies of certain health behaviors to prevent or delay cancer may be more reliable predictors of those behaviors. Clinicians should assess perceived efficacies of health behaviors in their interventions to improve healthy practices in the BRCA1/2 genetic testing population.

  6. Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results.

    Science.gov (United States)

    Bradbury, A R; Patrick-Miller, L; Fetzer, D; Egleston, B; Cummings, S A; Forman, A; Bealin, L; Peterson, C; Corbman, M; O'Connell, J; Daly, M B

    2011-02-01

    BRCA1/2 test disclosure has, historically, been conducted in-person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased. Semi-structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions. One hundred and ninety-four genetic counselors completed self-administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre-test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty-two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted. © 2010 John Wiley & Sons A/S.

  7. Short report: Follow-up of Bahamian women with a BRCA1 or BRCA2 mutation.

    Science.gov (United States)

    Narod, Steven A; Butler, Raleigh; Bobrowski, David; Akbari, Mohammad R; Curling, DuVaughan; Lunn, John; Ho, Catherine; Panahi, Sara; Llacuachaqui, Marcia; Donenberg, Talia; Hurley, Judith

    2017-12-20

    We sought to determine to what extent the knowledge of carrying a BRCA1 or BRCA2 mutation influences the uptake of preventive surgeries in Bahamian women, including bilateral salpingo-oophorectomy and bilateral mastectomy. The study population consisted of 78 female residents of the Bahamas for whom a BRCA1 or BRCA2 mutation had been detected between 2004 and 2014. The mean age of the 78 participants at the time of genetic testing was 46 years (age range 22-73 years). The mean time of follow-up was 4.4 years. Of the 78 study participants, 19 women had a bilateral salpingo-oophorectomy (24%). Seven out of 37 patients who had unilateral breast cancer chose to remove the unaffected contralateral breast (19%). Three of 13 patients with no history of breast cancer chose to have a prophylactic bilateral mastectomy (23%). Preventive surgery is an acceptable option for a significant proportion of Bahamian women with a BRCA1 or BRCA2 mutation. It will be important to identify and reduce barriers to preventive surgery in the Bahamas in order that the benefit of getting testing can be fully realized. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  8. [Genes beyond BRCA1 and BRCA2 for hereditary breast cancer].

    Science.gov (United States)

    Simon, Katharina; Geigl, Jochen B; Pristauz, Gunda

    2010-11-01

    germline mutations in the tumor suppressor genes BRCA1 and BRCA2 are identified in less than 50% of hereditary breast cancer cases. Besides BRCA1/2 further high-risk breast cancer genes are known; however they account only for a small fraction of inherited breast cancer cases. Most of them are involved in rare cancer predisposition syndromes. Moderate and low-risk breast cancer genes confer modest cancer risk up to 10% and may be more relevant due to polygenic inheritance. The majority of hereditary breast cancer cases are still caused by unknown genes. genetic testing of other known genes is not yet routinely performed in families tested negative for BRCA1/2-mutations, but can be recommended in special patients. In case of a calculated high-risk situation, participation in an early-detection screening program should be recommended. genetic susceptibility to breast cancer is heterogeneous and conferred by a large number of identified and yet undetected genes.

  9. Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1

    Science.gov (United States)

    Cantor, Sharon B; Guillemette, Shawna

    2011-01-01

    It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1–FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression. PMID:21345144

  10. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

    DEFF Research Database (Denmark)

    Björkman, Andrea; Qvist, Per; Du, Likun

    2015-01-01

    Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the se......Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement...... of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast...... cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism...

  11. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...... by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c...... to have no or an uncertain effect on the protein level, whereas one variant (c.5072C>T/p.Thr1691Ile) were shown to have a strong effect on the protein level as well. In conclusion, our study emphasizes that in silico splicing prediction and mini-gene splicing analysis are important for the classification...

  12. Expression of TRAF6 and ubiquitin mRNA in skeletal muscle of gastric cancer patients

    Directory of Open Access Journals (Sweden)

    Sun Yuan-Shui

    2012-09-01

    Full Text Available Abstract Objective To investigate the prognostic significance of tumor necrosis factor receptor (TNFR,-associated factor 6 (TRAF6,-and ubiquitin in gastric cancer patients. Methods Biopsies of the rectus abdominis muscle were obtained intra operatively from 102 gastric cancer patients and 29 subjects undergoing surgery for benign abdominal diseases, and muscle TRAF6 and ubiquitin mRNA expression and proteasome proteolytic activities were assessed. Results TRAF6 was significantly upregulated in muscle of gastric cancer compared with the control muscles. TRAF6 was upregulated in 67.65% (69/102 muscle of gastric cancer. Over expression of TRAF6 in muscles of gastric cancer were associated with TNM stage, level of serum albumin and percent of weight loss. Ubiquitin was significantly upregulated in muscle of gastric cancer compared with the control muscles. Ubiquitin was upregulated in 58.82% (60/102 muscles of gastric cancer. Over expression of ubiquitin in muscles of gastric cancer were associated with TNM (Tumor-Node-Metastasis stage and weight loss. There was significant relation between TRAF6 and ubiquitin expression. Conclusions We found a positive correlation between TRAF6 and ubiquitin expression, suggesting that TRAF6 may up regulates ubiquitin activity in cancer cachexia. While more investigations are required to understand its mechanisms of TRAF6 and ubiquitin in skeletal muscle. Correct the catabolic-anabolic imbalance is essential for the effective treatment of cancer cachexia.

  13. Accuracy of BRCA1/2 mutation prediction models for different ethnicities and genders: experience in a southern Chinese cohort.

    Science.gov (United States)

    Kwong, Ava; Wong, Connie H N; Suen, Dacita T K; Co, Michael; Kurian, Allison W; West, Dee W; Ford, James M

    2012-04-01

    BRCA1/2 mutation prediction models (BRCAPRO, Myriad II, Couch, Shattuck-Eidens, BOADICEA) are well established in western cohorts to estimate the probability of BRCA1/2 mutations. Results are conflicting in Asian populations. Most studies did not account for gender-specific prediction. We evaluated the performance of these models in a Chinese cohort, including males, before BRCA1/2 mutation testing. The five risk models were used to calculate the probability of BRCA mutations in probands with breast and ovarian cancers; 267 were non-BRCA mutation carriers (247 females and 20 males) and 43 were BRCA mutation carriers (38 females and 5 males). Mean BRCA prediction scores for all models were statistically better for carriers than noncarriers for females but not for males. BRCAPRO overestimated the numbers of female BRCA1/2 mutation carriers at thresholds ≥20% but underestimated if different ethnic groups and genders.

  14. Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Jønson, Lars; Ejlertsen, Bent

    2010-01-01

    Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. Here we report the first identification of a Danish...... breast and ovarian cancer family heterozygote for mutations in the BRCA1 and BRCA2 genes. The BRCA1 nucleotide 5215G > A/c.5096G > A mutation results in the missense mutation Arg1699Gln, while the BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G is novel. Exon trapping experiments and reverse transcriptase...... (RT)-PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family...

  15. Next-Generation Sequencing-Based Detection of Germline Copy Number Variations in BRCA1/BRCA2

    DEFF Research Database (Denmark)

    Schmidt, Ane Y; Hansen, Thomas V O; Ahlborn, Lise B

    2017-01-01

    identified by MLPA in 48 Danish breast and/or ovarian cancer families were analyzed. Moreover, 120 patient samples previously determined as negative for BRCA1/BRCA2 CNVs by MLPA were included in the analysis. Comparison of the NGS data with the data from MLPA revealed that the sensitivity was 100%, whereas......Genetic testing of BRCA1/2 includes screening for single nucleotide variants and small insertions/deletions and for larger copy number variations (CNVs), primarily by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). With the advent of next-generation sequencing (NGS...... the specificity was 95%. Taken together, this study validates a one-step bioinformatics work-flow to call germline BRCA1/2 CNVs using data obtained by NGS of a breast cancer gene panel. The work-flow represents a robust and easy-to-use method for full BRCA1/2 screening, which can be easily implemented in routine...

  16. Population-based study of BRCA1/2 mutations: family history based criteria identify minority of mutation carriers.

    Science.gov (United States)

    Mateju, M; Stribrna, J; Zikan, M; Kleibl, Z; Janatova, M; Kormunda, S; Novotny, J; Soucek, P; Petruzelka, L; Pohlreich, P

    2010-01-01

    The two major susceptibility genes, BRCA1 and BRCA2, are involved in hereditary breast and ovarian cancer syndrome. Early detection of mutation carriers has crucial clinical importance, as it allows identification of women who may benefit from intensive clinical follow-up or prophylactic surgery. Generally accepted inclusion criteria for BRCA1/2 mutation testing are based either upon family history of breast or ovarian cancer or young age at cancer diagnosis. In order to analyze the impact of BRCA1/2 mutations on breast cancer development in the Czech population and to confront the clinical and histopathological data of mutation carriers with current criteria for mutation testing we examined the frequency of mutations in unselected breast cancer cases. Mutational analysis of BRCA1/2 genes performed in 679 unselected female breast cancer patients included all recurrent deleterious alterations previously identified in the Prague area and truncating mutations in the whole exon 11 of BRCA1. Within analyzed gene sequences more than 80% of mutations were identified previously in high-risk patients. A total of 16 breast cancer patients (2.4%) carried a mutation. BRCA1 mutations were identified in 14 (2.1%) whereas BRCA2 in 2 (0.3%) women. Family history of ovarian cancer was a strong predictor of a BRCA1/2 mutation (OR = 8.3; p = 0.01), however, family history of breast cancer was not indicative of carrier status. A significant association between medullary breast cancer and mutation status was observed. Current criteria for BRCA1/2 mutation testing would distinguish only 6 out of 16 (37.5%) carriers identified in our study. Ten breast cancer patients with confirmed BRCA1/2 germ-line mutation exhibited no clinical characteristics that would predict their carrier status. Therefore, we believe that the testing for BRCA1/2 mutations in the Czech Republic may not be restricted only to high-risk patients. Our results indicate that analysis of locally prevalent BRCA1

  17. Ets-1 mRNA expression in effusions of serous ovarian carcinoma patients is a marker of poor outcome.

    Science.gov (United States)

    Davidson, B; Risberg, B; Goldberg, I; Nesland, J M; Berner, A; Tropé, C G; Kristensen, G B; Bryne, M; Reich, R

    2001-12-01

    Ets-1 proto-oncogene is a transcription factor with a role in the activation of metastasis-associated molecules. We recently found that Ets-1 mRNA expression in solid tumors is a marker of poor prognosis in ovarian carcinoma. The objective of this study was to compare the expression of Ets-1 mRNA in effusions and primary and metastatic tumors of serous ovarian carcinoma patients and to evaluate its prognostic role in effusions. Sections from 67 malignant effusions and 90 primary and metastatic lesions were evaluated for expression of Ets-1 using mRNA in situ hybridization. Expression of Ets-1 mRNA was detected in carcinoma cells in 24 of 67 (36%) effusions. Expression in cancer cells was similar in peritoneal and pleural effusions. In solid lesions Ets-1 expression was detected in both tumor cells and stromal cells in 34 of 90 (38%) lesions. Ets-1 expression in tumor cells showed a strong association with that of stromal cells (p <0.001). Ets-1 expression in effusions showed an association with mRNA expression of basic fibroblast growth factor, previously studied in this patient cohort (p = 0.019). Ets-1 expression in solid lesions showed an association with mRNA expression of vascular endothelial growth factor (p <0.001 for both carcinoma and stromal cells), basic fibroblast growth factor (p = 0.007 for carcinoma cells, p = 0.006 for stromal cells), and interleukin-8 (IL-8) (p = 0.001 for tumor cells). Ets-1 mRNA showed upregulation in metastases when compared with effusion specimens (p = 0.028). In univariate survival analysis Ets-1 expression in carcinoma cells in effusions correlated with poor survival (p = 0.003). Our findings confirm the role of Ets-1 as a novel prognostic marker in advanced-stage ovarian carcinoma and extend it to effusion specimens. The elevated expression in solid metastases supports a central role in tumor progression as well. The association between Ets-1 mRNA expression and the expression of angiogenic genes, documented also in our

  18. O-methylguanine-DNA methyltransferase (MGMT mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation.

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    Simone Kreth

    2011-02-01

    Full Text Available We analyzed prospectively whether MGMT (O(6-methylguanine-DNA methyltransferase mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylation is associated with upregulation of DNMT expression.ADULT PATIENTS WITH A HISTOLOGICALLY PROVEN MALIGNANT ASTROCYTOMA (GLIOBLASTOMA: N = 53, anaplastic astrocytoma: N = 10 were included. MGMT promoter methylation was determined by methylation-specific PCR (MSP and sequencing analysis. Expression of MGMT and DNMTs mRNA were analysed by real-time qPCR. Prognostic factors were obtained from proportional hazards models. Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the Cancer Genome Atlas (TCGA database (N = 229 glioblastomas. Low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001; the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001; however, discordant findings were seen in 12 glioblastoma patients: Patients with methylated tumors with high MGMT mRNA expression (N = 6 did significantly worse than those with low transcriptional activity (p<0.01. Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6 did better than their counterparts. A nearly identical frequency of concordant and discordant findings was obtained by analyzing the TCGA database (p<0.0001. Expression of DNMT1 and DNMT3b was strongly upregulated in tumor tissue, but not correlated with MGMT promoter methylation and MGMT mRNA expression.MGMT mRNA expression plays a direct

  19. Oxidative stress induced Interleukin-32 mRNA expression in human bronchial epithelial cells

    Science.gov (United States)

    2012-01-01

    Background Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and persistent inflammation in the airways and lung parenchyma. Oxidative stress contributes to the pathogenesis of COPD. Interleukin (IL)-32 expression has been reported to increase in the lung tissue of patients with COPD. Here, we show that IFNγ upregulated IL-32 expression and that oxidative stress augmented IFNγ-induced-IL-32 expression in airway epithelial cells. We further investigated transcriptional regulation responsible for IFNγ induced IL-32 expression in human airway epithelial cells. Methods Human bronchial epithelial (HBE) cells were stimulated with H2O2 and IFNγ, and IL-32 expression was evaluated. The cell viability was confirmed by MTT assay. The intracellular signaling pathways regulating IL-32 expression were investigated by examining the regulatory effects of MAPK inhibitors and JAK inhibitor after treatment with H2O2 and IFNγ, and by using a ChIP assay to identify transcription factors (i.e. c-Jun, CREB) binding to the IL-32 promoter. Promoter activity assays were conducted after mutations were introduced into binding sites of c-Jun and CREB in the IL-32 promoter. IL-32 expression was also examined in HBE cells in which the expression of either c-Jun or CREB was knocked out by siRNA of indicated transcription factors. Results There were no significant differences of cell viability among groups. After stimulation with H2O2 or IFNγ for 48 hours, IL-32 expression in HBE cells was increased by IFNγ and synergistically upregulated by the addition of H2O2. The H2O2 augmented IFNγ induced IL-32 mRNA expression was suppressed by a JNK inhibitor, but not by MEK inhibitor, p38 inhibitor, and JAK inhibitor I. Significant binding of c-Jun and CREB to the IL-32 promoter was observed in the IFNγ + H2O2 stimulated HBE cells. Introducing mutations into the c-Jun/CREB binding sites in the IL-32 promoter prominently suppressed its transcriptional activity

  20. Modulation of the BRCA1 Protein and Induction of Apoptosis in Triple Negative Breast Cancer Cell Lines by the Polyphenolic Compound Curcumin

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    Danica L. Rowe

    2009-09-01

    Full Text Available In the current study, we sought to examine the effects of curcumin in a specific type of breast cancer called triple negative breast cancer. These cancers lack expression of the estrogen and progesterone receptors and do not over-express HER2. Current treatment for triple negative breast cancers is limited to cytotoxic chemotherapy, and upon relapse, there are not any therapies currently available. We demonstrate here that the bioactive food compound curcumin induces DNA damage in triple negative breast cancer cells in association with phosphorylation, increased expression, and cytoplasmic retention of the BRCA1 protein. In addition, curcumin promotes apoptosis and prevents anchorage-independent growth and migration of triple negative breast cancer cells. Apoptosis and BRCA1 modulation were not observed in non-transformed mammary epithelial cells, suggesting curcumin may have