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  1. Article ; Online: Chromatin Organization and Transcriptional Programming of Breast Cancer Cell Identity.

    Bobbitt, Jessica R / Seachrist, Darcie D / Keri, Ruth A

    Endocrinology

    2023  Volume 164, Issue 8

    Abstract: The advent of sequencing technologies for assessing chromosome conformations has provided a wealth of information on the organization of the 3-dimensional genome and its role in cancer progression. It is now known that changes in chromatin folding and ... ...

    Abstract The advent of sequencing technologies for assessing chromosome conformations has provided a wealth of information on the organization of the 3-dimensional genome and its role in cancer progression. It is now known that changes in chromatin folding and accessibility can promote aberrant activation or repression of transcriptional programs that can drive tumorigenesis and progression in diverse cancers. This includes breast cancer, which comprises several distinct subtypes defined by their unique transcriptomes that dictate treatment response and patient outcomes. Of these, basal-like breast cancer is an aggressive subtype controlled by a pluripotency-enforcing transcriptome. Meanwhile, the more differentiated luminal subtype of breast cancer is driven by an estrogen receptor-dominated transcriptome that underlies its responsiveness to antihormone therapies and conveys improved patient outcomes. Despite the clear differences in molecular signatures, the genesis of each subtype from normal mammary epithelial cells remains unclear. Recent technical advances have revealed key distinctions in chromatin folding and organization between subtypes that could underlie their transcriptomic and, hence, phenotypic differences. These studies also suggest that proteins controlling particular chromatin states may be useful targets for treating aggressive disease. In this review, we explore the current state of understanding of chromatin architecture in breast cancer subtypes and its potential role in defining their phenotypic characteristics.
    MeSH term(s) Humans ; Female ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Breast/metabolism ; Chromatin/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic
    Chemical Substances Chromatin
    Language English
    Publishing date 2023-07-11
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqad100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The effect of prolonged exposure on sodium dodecyl sulfate penetration into human skin.

    Morris, Stephanie A V / Bobbitt, Jessica R / Ananthapadmanabhan, K P / Kasting, Gerald B

    Toxicology in vitro : an international journal published in association with BIBRA

    2021  Volume 77, Page(s) 105246

    Abstract: The purpose of this study was to examine the effect of prolonged surfactant exposure on mechanisms of anionic surfactant penetration into human skin. A radiolabeled probe (14-carbon sodium dodecyl sulfate ( ...

    Abstract The purpose of this study was to examine the effect of prolonged surfactant exposure on mechanisms of anionic surfactant penetration into human skin. A radiolabeled probe (14-carbon sodium dodecyl sulfate (
    MeSH term(s) Carbon Radioisotopes ; Dose-Response Relationship, Drug ; Humans ; Skin/drug effects ; Skin/metabolism ; Skin Absorption ; Sodium Dodecyl Sulfate/adverse effects ; Sodium Dodecyl Sulfate/pharmacokinetics
    Chemical Substances Carbon Radioisotopes ; Sodium Dodecyl Sulfate (368GB5141J)
    Language English
    Publishing date 2021-09-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2021.105246
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2223: Show issues Location:
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  3. Article ; Online: Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction.

    Piemonte, Katrina M / Webb, Bryan M / Bobbitt, Jessica R / Majmudar, Parth R / Cuellar-Vite, Leslie / Bryson, Benjamin L / Latina, Nicholas C / Seachrist, Darcie D / Keri, Ruth A

    The Journal of biological chemistry

    2023  Volume 299, Issue 7, Page(s) 104834

    Abstract: Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. ...

    Abstract Chromatin organization is highly dynamic and modulates DNA replication, transcription, and chromosome segregation. Condensin is essential for chromosome assembly during mitosis and meiosis, as well as maintenance of chromosome structure during interphase. While it is well established that sustained condensin expression is necessary to ensure chromosome stability, the mechanisms that control its expression are not yet known. Herein, we report that disruption of cyclin-dependent kinase 7 (CDK7), the core catalytic subunit of CDK-activating kinase, leads to reduced transcription of several condensin subunits, including structural maintenance of chromosomes 2 (SMC2). Live and static microscopy revealed that inhibiting CDK7 signaling prolongs mitosis and induces chromatin bridge formation, DNA double-strand breaks, and abnormal nuclear features, all of which are indicative of mitotic catastrophe and chromosome instability. Affirming the importance of condensin regulation by CDK7, genetic suppression of the expression of SMC2, a core subunit of this complex, phenocopies CDK7 inhibition. Moreover, analysis of genome-wide chromatin conformation using Hi-C revealed that sustained activity of CDK7 is necessary to maintain chromatin sublooping, a function that is ascribed to condensin. Notably, the regulation of condensin subunit gene expression is independent of superenhancers. Together, these studies reveal a new role for CDK7 in sustaining chromatin configuration by ensuring the expression of condensin genes, including SMC2.
    MeSH term(s) Chromatin/genetics ; Chromatin/metabolism ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Mitosis/genetics ; Chromosomal Instability/genetics ; Signal Transduction ; Humans ; Cell Line, Tumor ; Gene Expression Regulation/genetics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Gene Silencing
    Chemical Substances Chromatin ; condensin complexes ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; CDK7 protein, human ; SMC2 protein, human ; Cell Cycle Proteins
    Language English
    Publishing date 2023-05-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104834
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.108: Show issues Location:
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  4. Article ; Online: TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters.

    Webb, Bryan M / Bryson, Benjamin L / Williams-Medina, Eduardo / Bobbitt, Jessica R / Seachrist, Darcie D / Anstine, Lindsey J / Keri, Ruth A

    The Journal of biological chemistry

    2021  Volume 297, Issue 4, Page(s) 101162

    Abstract: Cyclin-dependent kinase 7 (CDK7) is a master regulatory kinase that drives cell cycle progression and stimulates expression of oncogenes in a myriad of cancers. Inhibitors of CDK7 (CDK7i) are currently in clinical trials; however, as with many cancer ... ...

    Abstract Cyclin-dependent kinase 7 (CDK7) is a master regulatory kinase that drives cell cycle progression and stimulates expression of oncogenes in a myriad of cancers. Inhibitors of CDK7 (CDK7i) are currently in clinical trials; however, as with many cancer therapies, patients will most likely experience recurrent disease due to acquired resistance. Identifying targets underlying CDK7i resistance will facilitate prospective development of new therapies that can circumvent such resistance. Here we utilized triple-negative breast cancer as a model to discern mechanisms of resistance as it has been previously shown to be highly responsive to CDK7 inhibitors. After generating cell lines with acquired resistance, high-throughput RNA sequencing revealed significant upregulation of genes associated with efflux pumps and transforming growth factor-beta (TGF-β) signaling pathways. Genetic silencing or pharmacological inhibition of ABCG2, an efflux pump associated with multidrug resistance, resensitized resistant cells to CDK7i, indicating a reliance on these transporters. Expression of activin A (INHBA), a member of the TGF-β family of ligands, was also induced, whereas its intrinsic inhibitor, follistatin (FST), was repressed. In resistant cells, increased phosphorylation of SMAD3, a downstream mediator, confirmed an increase in activin signaling, and phosphorylated SMAD3 directly bound the ABCG2 promoter regulatory region. Finally, pharmacological inhibition of TGF-β/activin receptors or genetic silencing of SMAD4, a transcriptional partner of SMAD3, reversed the upregulation of ABCG2 in resistant cells and phenocopied ABCG2 inhibition. This study reveals that inhibiting the TGF-β/Activin-ABCG2 pathway is a potential avenue for preventing or overcoming resistance to CDK7 inhibitors.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily G, Member 2/biosynthesis ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; Cell Line, Tumor ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Inhibin-beta Subunits/genetics ; Inhibin-beta Subunits/metabolism ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Up-Regulation/drug effects
    Chemical Substances ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Protein Kinase Inhibitors ; Transforming Growth Factor beta ; inhibin beta A subunit ; Inhibin-beta Subunits (93443-12-0) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; cyclin-dependent kinase-activating kinase (EC 2.7.11.22)
    Language English
    Publishing date 2021-09-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2021.101162
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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