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  1. Article ; Online: Epigenetic regulation in estrogen receptor positive breast cancer--role in treatment response.

    Pathiraja, Thushangi N / Stearns, Vered / Oesterreich, Steffi

    Journal of mammary gland biology and neoplasia

    2010  Volume 15, Issue 1, Page(s) 35–47

    Abstract: Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine ... ...

    Abstract Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine therapy remains a major challenge in the clinic. A number of possible mechanisms for drug resistance have been described, which include activation of growth factor receptor pathways, overexpression of ER coactivators, and metabolic resistance due to polymorphisms in metabolizing enzymes. While many of these changes are caused by genetic alterations, there is also increasing evidence to implicate epigenetic gene regulatory mechanisms in the development of endocrine resistance. Since epigenetic modifications are easier to reverse than genetic mutations, they are appealing therapeutic targets, and thus future improvements in medical care for breast cancer patients will depend upon a better understanding of the roles epigenetic modifications play in endocrine resistance. In this review we will focus on recent advances made in the understanding of epigenetic gene regulation in estrogen response and endocrine resistance in breast cancer. We will also summarize current clinical-translational advances in epigenetic therapy, and discuss potential future clinical use of epigenetic changes as therapeutic targets, especially with respect to endocrine treatment.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents, Hormonal/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Drug Resistance, Neoplasm ; Epigenesis, Genetic/physiology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/genetics ; Receptors, Progesterone/metabolism ; Treatment Outcome
    Chemical Substances Antineoplastic Agents ; Antineoplastic Agents, Hormonal ; Histone Deacetylase Inhibitors ; Receptors, Estrogen ; Receptors, Progesterone
    Language English
    Publishing date 2010-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1327345-0
    ISSN 1573-7039 ; 1083-3021
    ISSN (online) 1573-7039
    ISSN 1083-3021
    DOI 10.1007/s10911-010-9166-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Epigenetic Regulation in Estrogen Receptor Positive Breast Cancer—Role in Treatment Response

    Pathiraja, Thushangi N / Stearns, Vered / Oesterreich, Steffi

    Journal of mammary gland biology and neoplasia. 2010 Mar., v. 15, no. 1

    2010  

    Abstract: Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine ... ...

    Abstract Recent advances in breast cancer treatment have allowed increasing numbers of patients with estrogen receptor (ER) positive (+) breast cancer to receive various forms of endocrine therapy. Unfortunately, de novo and acquired resistance to endocrine therapy remains a major challenge in the clinic. A number of possible mechanisms for drug resistance have been described, which include activation of growth factor receptor pathways, overexpression of ER coactivators, and metabolic resistance due to polymorphisms in metabolizing enzymes. While many of these changes are caused by genetic alterations, there is also increasing evidence to implicate epigenetic gene regulatory mechanisms in the development of endocrine resistance. Since epigenetic modifications are easier to reverse than genetic mutations, they are appealing therapeutic targets, and thus future improvements in medical care for breast cancer patients will depend upon a better understanding of the roles epigenetic modifications play in endocrine resistance. In this review we will focus on recent advances made in the understanding of epigenetic gene regulation in estrogen response and endocrine resistance in breast cancer. We will also summarize current clinical-translational advances in epigenetic therapy, and discuss potential future clinical use of epigenetic changes as therapeutic targets, especially with respect to endocrine treatment.
    Language English
    Dates of publication 2010-03
    Size p. 35-47.
    Publisher Springer US
    Publishing place Boston
    Document type Article
    ZDB-ID 1327345-0
    ISSN 1083-3021
    ISSN 1083-3021
    DOI 10.1007/s10911-010-9166-0
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia.

    Ko, Tun Kiat / Javed, Asif / Lee, Kian Leong / Pathiraja, Thushangi N / Liu, Xingliang / Malik, Simeen / Soh, Sheila Xinxuan / Heng, Xiu Ting / Takahashi, Naoto / Tan, Joanna H J / Bhatia, Ravi / Khng, Alexis J / Chng, Wee-Joo / Sia, Yee Yen / Fruman, David A / Ng, King Pan / Chan, Zhu En / Xie, Kim Jiajing / Hoi, Qiangze /
    Chan, Cheryl Xueli / Teo, Audrey S M / Velazquez Camacho, Oscar / Meah, Wee Yang / Khor, Chiea Chuen / Ong, Chin Thing J / Soon, Wei Jia W / Tan, Patrick / Ng, Pauline C / Chuah, Charles / Hillmer, Axel M / Ong, S Tiong

    Blood

    2020  Volume 135, Issue 26, Page(s) 2337–2353

    Abstract: Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations ...

    Abstract Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.
    MeSH term(s) Blast Crisis/genetics ; Cell Differentiation ; Chromatin Immunoprecipitation ; DNA Methylation ; Datasets as Topic ; Enhancer of Zeste Homolog 2 Protein/physiology ; Gene Dosage ; Gene Expression Regulation, Leukemic/genetics ; Gene Ontology ; High-Throughput Nucleotide Sequencing ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Mutation ; Polycomb Repressive Complex 1/genetics ; Polycomb Repressive Complex 1/physiology ; Polycomb Repressive Complex 2/genetics ; Polycomb Repressive Complex 2/physiology ; Transcriptome ; Whole Exome Sequencing ; Whole Genome Sequencing
    Chemical Substances BMI1 protein, human ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
    Language English
    Publishing date 2020-03-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2020004834
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A Role for Histone H2B Variants in Endocrine-Resistant Breast Cancer.

    Nayak, Shweta R / Harrington, Emily / Boone, David / Hartmaier, Ryan / Chen, Jian / Pathiraja, Thushangi N / Cooper, Kristine L / Fine, Jeffrey L / Sanfilippo, Joseph / Davidson, Nancy E / Lee, Adrian V / Dabbs, David / Oesterreich, Steffi

    Hormones & cancer

    2015  Volume 6, Issue 5-6, Page(s) 214–224

    Abstract: ... expression in resistant (n = 19) compared with sensitive (n = 37) tumors (p = 0.01). Using nanostring ...

    Abstract Acquired resistance to aromatase inhibitors (AIs) remains a major clinical problem in the treatment of estrogen receptor-positive (ER+) breast cancer. We and others have previously reported widespread changes in DNA methylation using breast cancer cell line models of endocrine resistance. Here, we show that the histone variant HIST1H2BE is hypomethylated in estrogen deprivation-resistant C4-12 and long-term estrogen-deprived (LTED) cells compared with parental MCF-7 cells. As expected, this hypomethylation associates with increased expression of HIST1H2BE in C4-12 and LTED cells. Both overexpression and downregulation of HIST1H2BE caused decreased proliferation in breast cancer cell lines suggesting the need for tightly controlled expression of this histone variant. Gene expression analysis showed varied expression of HIST1H2BE in a large panel of breast cancer cell lines, without restriction to specific molecular subtypes. Analysis of HIST1H2BE messenger RNA (mRNA) expression in ER+ AI-treated breast tumors showed significantly higher expression in resistant (n = 19) compared with sensitive (n = 37) tumors (p = 0.01). Using nanostring analysis, we measured expression of all 61 histone variants in endocrine-resistant and endocrine-sensitive tumors. We found significant overexpression of 22 variant histone genes in tumors resistant to AI therapy. In silico The Cancer Genome Atlas (TCGA) analysis showed frequent amplification of the HIST1 locus. In summary, our studies show, for the first time, that overexpression of histone variants might be important in endocrine response in ER+ breast cancer, and that overexpression is at least in part mediated via epigenetic mechanisms and amplifications. Future studies addressing endocrine response should include a potential role of these currently understudied histone variants.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Agents, Hormonal/pharmacology ; Antineoplastic Agents, Hormonal/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Case-Control Studies ; Cell Line, Tumor ; Cell Proliferation ; Cluster Analysis ; Combined Modality Therapy ; DNA Methylation ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression ; Gene Expression Profiling ; Gene Knockdown Techniques ; Genetic Variation ; Histones/chemistry ; Histones/genetics ; Histones/metabolism ; Humans ; Middle Aged ; Multigene Family ; Neoplasm Grading ; Neoplasm Staging ; Sequence Analysis, DNA
    Chemical Substances Antineoplastic Agents, Hormonal ; Histones
    Language English
    Publishing date 2015-06-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2543318-0
    ISSN 1868-8500 ; 1868-8500
    ISSN (online) 1868-8500
    ISSN 1868-8500
    DOI 10.1007/s12672-015-0230-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Targeted DNA Methylation Screen in the Mouse Mammary Genome Reveals a Parity-Induced Hypermethylation of Igf1r That Persists Long after Parturition.

    Katz, Tiffany A / Liao, Serena G / Palmieri, Vincent J / Dearth, Robert K / Pathiraja, Thushangi N / Huo, Zhiguang / Shaw, Patricia / Small, Sarah / Davidson, Nancy E / Peters, David G / Tseng, George C / Oesterreich, Steffi / Lee, Adrian V

    Cancer prevention research (Philadelphia, Pa.)

    2015  Volume 8, Issue 10, Page(s) 1000–1009

    Abstract: The most effective natural prevention against breast cancer is an early first full-term pregnancy. Understanding how the protective effect is elicited will inform the development of new prevention strategies. To better understand the role of epigenetics ... ...

    Abstract The most effective natural prevention against breast cancer is an early first full-term pregnancy. Understanding how the protective effect is elicited will inform the development of new prevention strategies. To better understand the role of epigenetics in long-term protection, we investigated parity-induced DNA methylation in the mammary gland. FVB mice were bred or remained nulliparous and mammary glands harvested immediately after involution (early) or 6.5 months following involution (late), allowing identification of both transient and persistent changes. Targeted DNA methylation (109 Mb of Ensemble regulatory features) analysis was performed using the SureSelectXT Mouse Methyl-seq assay and massively parallel sequencing. Two hundred sixty-nine genes were hypermethylated and 128 hypomethylated persistently at both the early and late time points. Pathway analysis of the persistently differentially methylated genes revealed Igf1r to be central to one of the top identified signaling networks, and Igf1r itself was one of the most significantly hypermethylated genes. Hypermethylation of Igf1r in the parous mammary gland was associated with a reduction of Igf1r mRNA expression. These data suggest that the IGF pathway is regulated at multiple levels during pregnancy and that its modification might be critical in the protective role of pregnancy. This supports the approach of lowering IGF action for prevention of breast cancer, a concept that is currently being tested clinically.
    MeSH term(s) Animals ; Breast Neoplasms/genetics ; DNA Methylation/genetics ; Female ; Genome ; Mammary Glands, Animal/metabolism ; Mice ; Parity/genetics ; Parturition ; Polymerase Chain Reaction ; Pregnancy ; Receptor, IGF Type 1/genetics
    Chemical Substances Receptor, IGF Type 1 (EC 2.7.10.1)
    Language English
    Publishing date 2015-08-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2434717-6
    ISSN 1940-6215 ; 1940-6207
    ISSN (online) 1940-6215
    ISSN 1940-6207
    DOI 10.1158/1940-6207.CAPR-15-0178
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients.

    Pathiraja, Thushangi N / Shetty, Priya B / Jelinek, Jaroslav / He, Rong / Hartmaier, Ryan / Margossian, Astrid L / Hilsenbeck, Susan G / Issa, Jean-Pierre J / Oesterreich, Steffi

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2011  Volume 17, Issue 12, Page(s) 4177–4186

    Abstract: ... expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent ... surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand ...

    Abstract Purpose: ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although PR is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, PRA and PRB, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.
    Experimental design: We conducted a cohort-based study to test for associations between PRA and PRB methylation, expression, and clinical outcome in tamoxifen-treated patients (n = 500), and in patients who underwent surgery only (n = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.
    Results: Low PR levels were significantly associated with worse outcome in all patients. PRA and PRB promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. PRA methylation was significantly associated with PRB methylation, although a subset of tumors had PRA only (3.9%) or PRB only (8.3%) methylated. Methylation of PRA, but not PRB was significantly associated with worse outcome in the tamoxifen-treated group.
    Conclusions: Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of PRA and PRB. Finally, this article shows for the first time that PRA methylation plays a unique role in tamoxifen-resistant breast cancer.
    MeSH term(s) Adult ; Aged ; Antineoplastic Agents, Hormonal/therapeutic use ; Breast Neoplasms/diagnosis ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/physiopathology ; DNA Methylation ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Gene Order ; Humans ; Middle Aged ; Prognosis ; Promoter Regions, Genetic/genetics ; Protein Isoforms/metabolism ; Receptors, Estrogen/genetics ; Receptors, Progesterone/genetics ; Receptors, Progesterone/metabolism ; Survival Analysis ; Tamoxifen/therapeutic use ; Treatment Outcome
    Chemical Substances Antineoplastic Agents, Hormonal ; Protein Isoforms ; Receptors, Estrogen ; Receptors, Progesterone ; Tamoxifen (094ZI81Y45)
    Language English
    Publishing date 2011-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-10-2950
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer.

    Pathiraja, Thushangi N / Nayak, Shweta R / Xi, Yuanxin / Jiang, Shiming / Garee, Jason P / Edwards, Dean P / Lee, Adrian V / Chen, Jian / Shea, Martin J / Santen, Richard J / Gannon, Frank / Kangaspeska, Sara / Jelinek, Jaroslav / Issa, Jean-Pierre J / Richer, Jennifer K / Elias, Anthony / McIlroy, Marie / Young, Leonie S / Davidson, Nancy E /
    Schiff, Rachel / Li, Wei / Oesterreich, Steffi

    Science translational medicine

    2014  Volume 6, Issue 229, Page(s) 229ra41

    Abstract: Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with ... ...

    Abstract Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Aromatase Inhibitors/pharmacology ; Aromatase Inhibitors/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Cellular Reprogramming/drug effects ; Cellular Reprogramming/genetics ; DNA Methylation/drug effects ; DNA Methylation/genetics ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic/drug effects ; Epigenesis, Genetic/genetics ; Estrogens/pharmacology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Silencing/drug effects ; Histones/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; MCF-7 Cells ; Mice ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Promoter Regions, Genetic ; Xenograft Model Antitumor Assays
    Chemical Substances Aromatase Inhibitors ; Estrogens ; HOXC10 protein, human ; Histones ; Homeodomain Proteins
    Language English
    Publishing date 2014-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.3008326
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

    Yao, Fei / Kausalya, Jaya P / Sia, Yee Yen / Teo, Audrey S M / Lee, Wah Heng / Ong, Alicia G M / Zhang, Zhenshui / Tan, Joanna H J / Li, Guoliang / Bertrand, Denis / Liu, Xingliang / Poh, Huay Mei / Guan, Peiyong / Zhu, Feng / Pathiraja, Thushangi Nadeera / Ariyaratne, Pramila N / Rao, Jaideepraj / Woo, Xing Yi / Cai, Shaojiang /
    Mulawadi, Fabianus H / Poh, Wan Ting / Veeravalli, Lavanya / Chan, Chee Seng / Lim, Seong Soo / Leong, See Ting / Neo, Say Chuan / Choi, Poh Sum D / Chew, Elaine G Y / Nagarajan, Niranjan / Jacques, Pierre-Étienne / So, Jimmy B Y / Ruan, Xiaoan / Yeoh, Khay Guan / Tan, Patrick / Sung, Wing-Kin / Hunziker, Walter / Ruan, Yijun / Hillmer, Axel M

    Cell reports

    2015  Volume 12, Issue 2, Page(s) 272–285

    Abstract: Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in ... ...

    Abstract Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.
    MeSH term(s) Amino Acid Sequence ; Animals ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Clathrin/pharmacology ; Claudins/genetics ; Claudins/metabolism ; Dogs ; Endocytosis/drug effects ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Epithelial-Mesenchymal Transition ; GTPase-Activating Proteins/genetics ; GTPase-Activating Proteins/metabolism ; HeLa Cells ; Humans ; MCF-7 Cells ; Madin Darby Canine Kidney Cells ; Molecular Sequence Data ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Phenotype ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; rhoA GTP-Binding Protein/antagonists & inhibitors ; rhoA GTP-Binding Protein/metabolism
    Chemical Substances ARHGAP26 protein, human ; CLDN18 protein, human ; Clathrin ; Claudins ; GTPase-Activating Proteins ; Oncogene Proteins, Fusion ; RHOA protein, human (124671-05-2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2015-07-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2015.06.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Recurrent Fusion Genes in Gastric Cancer

    Fei Yao / Jaya P. Kausalya / Yee Yen Sia / Audrey S.M. Teo / Wah Heng Lee / Alicia G.M. Ong / Zhenshui Zhang / Joanna H.J. Tan / Guoliang Li / Denis Bertrand / Xingliang Liu / Huay Mei Poh / Peiyong Guan / Feng Zhu / Thushangi Nadeera Pathiraja / Pramila N. Ariyaratne / Jaideepraj Rao / Xing Yi Woo / Shaojiang Cai /
    Fabianus H. Mulawadi / Wan Ting Poh / Lavanya Veeravalli / Chee Seng Chan / Seong Soo Lim / See Ting Leong / Say Chuan Neo / Poh Sum D. Choi / Elaine G.Y. Chew / Niranjan Nagarajan / Pierre-Étienne Jacques / Jimmy B.Y. So / Xiaoan Ruan / Khay Guan Yeoh / Patrick Tan / Wing-Kin Sung / Walter Hunziker / Yijun Ruan / Axel M. Hillmer

    Cell Reports, Vol 12, Iss 2, Pp 272-

    CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity

    2015  Volume 285

    Abstract: Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in ... ...

    Abstract Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed.
    Keywords Science ; Q ; Biology (General) ; QH301-705.5
    Publishing date 2015-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Recurrent Fusion Genes in Gastric Cancer

    Fei Yao / Jaya P. Kausalya / Yee Yen Sia / Audrey S.M. Teo / Wah Heng Lee / Alicia G.M. Ong / Zhenshui Zhang / Joanna H.J. Tan / Guoliang Li / Denis Bertrand / Xingliang Liu / Huay Mei Poh / Peiyong Guan / Feng Zhu / Thushangi Nadeera Pathiraja / Pramila N. Ariyaratne / Jaideepraj Rao / Xing Yi Woo / Shaojiang Cai /
    Fabianus H. Mulawadi / Wan Ting Poh / Lavanya Veeravalli / Chee Seng Chan / Seong Soo Lim / See Ting Leong / Say Chuan Neo / Poh Sum D. Choi / Elaine G.Y. Chew / Niranjan Nagarajan / Pierre-Étienne Jacques / Jimmy B.Y. So / Xiaoan Ruan / Khay Guan Yeoh / Patrick Tan / Wing-Kin Sung / Walter Hunziker / Yijun Ruan / Axel M. Hillmer

    Cell Reports, Vol 12, Iss 2, Pp 272-

    CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity

    2015  Volume 285

    Abstract: Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in ... ...

    Abstract Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H+ leakage, and the fusion might contribute to invasiveness once a cell is transformed.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2015-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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