• Title, Summary, Keyword: BRCA1

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Expression of DNA Damage Response Proteins and Associations with Clinicopathologic Characteristics in Chinese Familial Breast Cancer Patients with BRCA1/2 Mutations

  • Zhu, Xinyi;Tian, Tian;Ruan, Miao;Rao, Jia;Yang, Wentao;Cai, Xu;Sun, Menghong;Qin, Guangqi;Zhao, Zhonghua;Wu, Jiong;Shao, Zhimin;Shui, Ruohong;Hu, Zhen
    • Journal of Breast Cancer
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    • v.21 no.3
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    • pp.297-305
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    • 2018
  • Purpose: The characteristic expression of DNA damage response proteins in familial breast cancers with BRCA1, BRCA2, or non-BRCA1/2 mutations has not been analyzed in Chinese patients. Our study aimed to assess the differential expression of microcephalin 1 (BRIT1), ATM serine/threonine kinase (ATM), checkpoint kinase 2 (CHEK2), BRCA1, RAD51 recombinase (RAD51), and poly (ADP-ribose) polymerase 1 (PARP-1) and establish the profile of Chinese familial breast cancers with different mutation status. Methods: We constructed five tissue microarrays from 183 familial breast cancer patients (31 with BRCA1 mutations; 14 with BRCA2 mutations, and 138 with non-BRCA1/2 mutations). The DNA response and repair markers used for immunohistochemistry analysis included BRIT1, ATM, CHEK2, BRCA1, RAD51, and PARP-1. The expressions of these proteins were analyzed in BRCA1/2 mutated tumors. The association between pathologic characteristics with BRCA1/2 mutation status was also analyzed. Results: In familial breast cancer patients, BRCA1 mutated tumors were more frequent with high nuclear grade, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, low Ki-67, and positive CK5/6. BRCA1 mutated tumors had lower CHEK2 and higher cytoplasmic BRIT1 expression than BRCA2 and non-BRCA1/2 mutation tumors. BRCA2-associated tumors showed higher CHEK2 and cytoplasmic RAD51 expression than those in other groups. Nuclear PARP-1 expression in BRCA1/2-associated tumors was significantly higher than in non-BRCA1/2 mutation tumors. Moreover, we found quite a few of negative PARP-1 expression cases in BRCA1/2 mutated groups. Conclusion: The clinicopathologic findings of BRCA1-associated Chinese familial breast cancers were similar to the results of other studies. Chinese familial breast cancer patients with BRCA1/2 mutations might have distinctive expression of different DNA damage response proteins. The reduced expression of PARP-1 in Chinese BRCA1/2 mutated breast cancer patients could influence the therapeutic outcome of PARP-1 inhibitors.

Involvement of Brca1 in DNA Interstrand Cross-link Repair Through Homologous Recombination-independent Process (재조합 비의존적 경로를 통한 DNA 사슬간 교차결합 복구에의 Brca1단백질의 기능)

  • Yun, Jean-Ho
    • Journal of Life Science
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    • v.15 no.4
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    • pp.542-547
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    • 2005
  • Hypersensitivity of cells lacking Brcal to DNA interstrand .ross-link (ICL) agents such as cisplatin and mitomycin C(MMC) implicates the important role of Brcal in cellular response following ICL treatment. Brca1 plays an essential role in DNA double-strand break (DSB) repair through homologous recombination (HR)-dependent and -independent process. Recently, our group has been reported that Brca1 involves in cellular ICL response through HR-dependent repair process (Yun J. et at., Oncogene 2005). In this report, the involvement of Brca1 protein in HR-independent repair process is examined using isogenic $p53^{-/-}\;and\;p53^{-/-}\;Brcal^{-/-}$ mouse embryonic fibroblast (MEF) and psoralen cross-linked reporter reactivation assay. Brcal-deficient MEFs showed significantly low HR-independent repair activity compare to Brca1-proficient MEFs. Hypersensitivity to MMC and ICL reporter repair activity were restored by the reconstitution of Brca1 expression. Interestingly, MEFs expressing exon 11-deleted isoform of Brca1 $(Brca1^{\Delta11/\Delta11})$ showed high resistance to MMC and ICL reporter repair activity comparable to Brca1-reconstituted MEFs. Taken together, these results suggest that Brca1 involves in ICL repair through not only HR-dependent process but also HR-independent process using N-terminal RINC finger domain or C-terminal BRCT domain rather than exon 11 region which mediate interaction with Rad50.

A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer (젊은 한국인 유방암 환자에서 BRCA1/2 돌연변이와 호르몬 수용체, HER-2 상태에 관한 연구)

  • Choi, Doo-Ho;Jin, So-Young;Lee, Dong-Wha;Kim, Eun-Seog;Kim, Yong-Ho
    • Radiation Oncology Journal
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    • v.26 no.1
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    • pp.65-73
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    • 2008
  • Purpose: Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Materials and Methods: Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor(ER), progesterone receptor(PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. Results: There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history(4/14) and bilateral breast cancers(3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2-associated cancers demonstrated more expression of ER-negative(19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors(negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was not a prognostic factor. Conclusion: Breast cancer that occurs in women with a germline BRCA1 or BRCA2 mutations have recognizable immunohistochemical features, which may be useful in identifying individuals that are more likely to carry germline mutations. Although the BRCA1/2 mutation status was not a prognostic factor in Korean women with early-onset breast cancer, more cases with a longer follow-up period are needed for further study.

Impaired Spindle Checkpoint Response of Brca1-deficient Mouse Embryonic Fibroblasts (MEFs) to Nocodazole Treatment (Brca1 결손 세포주에서 nocodazole 처리에 의한 spindle checkpoint 활성화 연구)

  • Kim Myoung-Ae;Kim Hyunju;Yun Jeanho
    • Journal of Life Science
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    • v.16 no.1
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    • pp.12-16
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    • 2006
  • Genetic alternation of Brca1 predispose of breast and ovarian cancer. Brca1 plays critical role in cell cycle regulation following DNA damage. Previous studies revealed that Brca1 plays an important role in S phase and G2/M checkpoint regulation. However, whether Brca1 involves in spindle checkpoint is unclear. In this study, the role of Brca1 in cell cycle response following nocodazole, which is a reagent that depolymerizes microtubules and activates the spindle checkpoint, has been examined using wild type $p53^{-/-}\;and\;p53^{-/-}Brca1^{-/-}$ mouse embryonic fibroblasts (MEFs). While wild type and Brca1-proficient MEFs showed an acute mitotic arrest, Brca1-deficient MEFs failed to arrest at mitotic phase in response to nocodazole treatment. In double-thymidine block and nocodazole treatment experiment, a portion of $p53^{-/-}\;Brca1^{-/-}$ MEFs were clearly by-passed nocodazole induced mitotic arrest. Consistent with this, in morphologic analysis, $p53^{-/-}\;Brca1^{-/-}$ MEFs showed growing cell morphology after nocodazole treatment. Taken together, these results suggest that Brca1 protein is an important component for normal induction of spindlecheckpoint and impairment of Brca1 function could induce dysregulation of mitotic cell cycle that ultimately results in genomic instability.

BRCA1 and BRCA2 Common Mutations in Iranian Breast Cancer Patients: a Meta Analysis

  • Forat-Yazdi, Mohammad;Neamatzadeh, Hossein;Sheikhha, Mohammad Hasan;Zare-Shehneh, Masoud;Fattahi, Mortaza
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.3
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    • pp.1219-1224
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    • 2015
  • Background: To date several common mutations in BRCA1 and BRCA2 associated with breast cancer have been reported in different populations. However, the common BRCA1 and BRCA2 mutations among breast cancer patients in Iran have not been described in detail. Materials and Methods: To comprehensively assess the frequency and distribution of the most common BRCA1 and BRCA2 mutations in Iranian breast cancer patients, we conducted this meta-analysis on 13 relevant published studies indentified in a literature search on PubMed and SID. Results: A total of 11 BRCA1 and BRCA2 distinct common mutations were identified, reported twice or more in the articles, of which 10 (c.2311T>C, c.3113A>G, c.4308T>C, c.4837A>G, c.2612C>T, c.3119G>A, c.3548A>G, c.5213G>A c.IVS16-92A/G, and c.IVS16-68A/G) mutations were in BRCA1, and 1 (c.4770A>G) was in BRCA2. The mutations were in exon 11, exon 13, intron 16, and exon 20 of BRCA1 and exon 11 of BRCA2. All have been previously reported in different populations. Conclusions: These meta analysis results should be helpful in understanding the possibility of any first true founder mutation of BRCA1/BRCA2 in the Iranian population. In addition, they will be of significance for diagnostic testing, genetic counseling and for epidemiological studies.

Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

  • Erturk, Elif;Cecener, Gulsah;Polatkan, Volkan;Gokgoz, Sehsuvar;Egeli, Unal;Tunca, Berrin;Tezcan, Gulcin;Demirdogen, Elif;Ak, Secil;Tasdelen, Ismet
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.19
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    • pp.8319-8324
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    • 2014
  • Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs $c.^*1287C$ >T (rs12516) (BRCA1) and $c.^*105A$ >C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism $c.^*1287C$ >T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP $c.^*1287C$ >T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

Clinically Significant Unclassified Variants in BRCA1 and BRCA2 Genes among Korean Breast Cancer Patients

  • Yoon, Kyong-Ah;Park, Boyoung;Lee, Byung Il;Yang, Moon Jung;Kong, Sun-Young;Lee, Eun Sook
    • Cancer Research and Treatment
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    • v.49 no.3
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    • pp.627-634
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    • 2017
  • Purpose Unclassified variants (UVs) of BRCA1 and BRCA2 genes are not defined as pathogenic for breast cancer, and their clinical significance currently remains undefined. Therefore, this study was conducted to identify potentially pathogenic UVs by comparing their prevalence between breast cancer patients and controls. Materials and Methods A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. Genetic variants of BRCA genes that were categorized as unclassified according to the Breast Cancer Information Core database were selected based on allelic frequency, after which candidate variants were genotyped in 421 healthy controls. We also examined family members of the study participants. Finally, the effects of amino acid substitutions on protein structure and function were predicted in silico. Results Genetic tests revealed 33 UVs in BRCA1 and 47 in BRCA2. Among 15 candidates genotyped in healthy controls, c.5339T>C in BRCA1 and c.6029T>G, c.7522G>A in BRCA2 were not detected. Moreover, the c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. This nonsynonymous variant (Leu1780Pro) in the BRCA1 C-terminal domain was predicted to have an effect on BRCA1 protein structure/function. Conclusion This study showed that comparison of genotype frequency between cases and controls could help identify UVs of BRCA genes that are potentially pathogenic. Moreover, our findings suggest that c.5339T>C in BRCA1 might be a pathogenic variant for patients and their families.

Comparison of Clinical Outcomes of BRCA1/2 Pathologic Mutation, Variants of Unknown Significance, or Wild Type Epithelial Ovarian Cancer Patients

  • Eoh, Kyung Jin;Park, Hyung Seok;Park, Ji Soo;Lee, Seung-Tae;Han, Jeongwoo;Lee, Jung-Yun;Kim, Sang Wun;Kim, Sunghoon;Kim, Young Tae;Nam, Eun Ji
    • Cancer Research and Treatment
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    • v.49 no.2
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    • pp.408-415
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    • 2017
  • Purpose The purpose of this study was to investigate the clinical features of epithelial ovarian cancer (EOC) patients according to BRCA1/2 mutation status (mutation, variant of uncertain significance [VUS], or wild type). Materials and Methods We analyzed 116 patients whose BRCA1/2 genetic test results were available for mutation type and clinical features, including progression-free survival (PFS), overall survival (OS), and response rate. These characteristics were compared according to BRCA1/2 mutation status. Results Thirty-seven (37/116, 31.9%) BRCA1/2 mutations were identified (BRCA1, 30; BRCA2, 7). Mutation of c.3627_3628insA (p.Leu1209_Glu1210?fs) in BRCA1 was observed in five patients (5/37, 13.5%). Twenty-five patients had BRCA1/2 VUSs (25/116, 21.6%). Personal histories of breast cancer were observed in 48.6% of patients with BRCA1/2 mutation (18/37), 16.0% of patients with BRCA1/2 VUS (4/25), and 7.4% of patients with BRCA wild type (4/54) (p < 0.001). Patients with BRCA1/2 mutation showed longer OS than those with BRCA1/2 wild type (p=0.005). No significant differences were detected in PFS, OS, or response rates between patients with BRCA1/2 VUS and BRCA1/2 mutation (p=0.772, p=0.459, and p=0.898, respectively). Conclusion Patients with BRCA1/2 mutation had longer OS than those with BRCA1/2wild type. Patients with BRCA1/2 mutation and BRCA1/2 VUS displayed similar prognoses.

Egr-1 regulates the transcription of the BRCA1 gene by etoposide

  • Shin, Soon Young;Kim, Chang Gun;Lee, Young Han
    • BMB Reports
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    • v.46 no.2
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    • pp.92-96
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    • 2013
  • The breast cancer susceptibility gene BRCA1 encodes a nuclear protein, which functions as a tumor suppressor and is involved in gene transcription and DNA repair processes. Many families with inherited breast and ovarian cancers have mutations in the BRCA1 gene. However, only a few studies have reported on the mechanism underlying the regulation of BRCA1 expression in humans. In this study, we investigated the transcriptional regulation of BRCA1 in HeLa cells treated with etoposide. We found that three Egr-1-binding sequences (EBSs) were located at -1031, -1005, and -385 within the enhancer region of the BRCA1 gene. Forced expression of Egr-1 stimulated the BRCA1 promoter activity. EMSA data showed that Egr-1 bound directly to the EBS within the BRCA1 gene. Knockdown of Egr-1 through the expression of a small hairpin RNA (shRNA) attenuated etoposide-induced BRCA1 promoter activity. We conclude that Egr-1 targets the BRCA1 gene in HeLa cells exposed to etoposide.

X-linked Gene Expression Profiles by RNAi-Mediated BRCA1 Knockdown in MCF7 Cells

  • Song, Min-Ae;Park, Jung-Hoon;Ahn, Hee-Jeong;Ko, Jung-Jae;Lee, Su-Man
    • Genomics & Informatics
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    • v.3 no.4
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    • pp.154-158
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    • 2005
  • Germ-line mutations of the BRCA1 gene confer an increased risk for breast and ovarian cancers. BRCA1 in female cells is directly related with the maintenance of the inactive X chromosome (Xi). The effect by the loss of the BRCA1 function on the X chromosome gene expression remains unclear in cancer cells. We attempted to investigate the expression pattern of the X-linked genes by performing BRCA1 knockdown via RNA interference in the MCF7 breast cancer cell line. The transcriptional and translational levels of BRCA1 were decreased over 95% in the MCF7 cells after BRCA1 knockdown. The expression patterns of one hundred ninety X-linked genes were profiled by the X chromosome-specific cDNA arrays. A total of seven percent of the X-linked genes (14/190) were aberrantly expressed by over 2-fold in the MCF7-BRCA1 knockdown cells, which contained two up-regulated genes (2/190, 1 %) and 12 down-regulated genes (12/190, 6.3%). It is interesting that 72% of the aberrantly expressed X-linked genes were located on the Xq (10/14,) region. Our data suggests that BRCA1 may not be important to maintain X chromosome inactivation in cancer because the BRCA1 knockdown did increase the expression of the only one percent of X-linked genes in the human breast cancer cells.