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  1. Article ; Online: Who is in the driver's seat in 8p12 amplifications? ZNF703 in luminal B breast tumors.

    Bazarov, Alexey V / Yaswen, Paul

    Breast cancer research : BCR

    2011  Volume 13, Issue 3, Page(s) 308

    Abstract: Two recent reports identify ZNF703 as an oncogene driving selection of frequent chromosome 8p12 amplifications in luminal B breast tumors. The estrogen-responsive ZNF703 gene encodes a transcriptional cofactor that, when overexpressed, induces cell ... ...

    Abstract Two recent reports identify ZNF703 as an oncogene driving selection of frequent chromosome 8p12 amplifications in luminal B breast tumors. The estrogen-responsive ZNF703 gene encodes a transcriptional cofactor that, when overexpressed, induces cell proliferation and interferes with transforming growth factor beta signaling. In MCF7 cells, increased ZNF703 expression results in activation of genes involved in stem cell self-renewal - while in primary human mammary epithelial cells, ZNF703 increases the ratio of luminal to basal progenitors. Expression of the murine homolog of ZNF703 reduces cell adhesion and promotes metastasis. ZNF703 overexpression thus alters regulation of proliferation and differentiation in luminal B tumors.
    MeSH term(s) Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Adhesion/genetics ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation ; Chromosomes, Human, Pair 8/genetics ; Female ; Gene Amplification ; Humans ; Mice ; Neoplasm Metastasis ; Neoplastic Stem Cells/metabolism ; Signal Transduction/genetics ; Transcription Factors/biosynthesis ; Transforming Growth Factor beta/metabolism
    Chemical Substances Carrier Proteins ; Transcription Factors ; Transforming Growth Factor beta ; ZNF703 protein, human
    Language English
    Publishing date 2011-05-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 2015059-3
    ISSN 1465-542X ; 1465-5411
    ISSN (online) 1465-542X
    ISSN 1465-5411
    DOI 10.1186/bcr2873
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A Simple Three-dimensional Hydrogel Platform Enables

    Hribar, Kolin C / Wheeler, Christopher J / Bazarov, Alexey / Varshneya, Kunal / Yamada, Ryosuke / Buckley, Padraig / Patil, Chirag G

    Molecular cancer therapeutics

    2019  Volume 18, Issue 3, Page(s) 718–725

    Abstract: A cell culture platform that ... ...

    Abstract A cell culture platform that enables
    MeSH term(s) Aged ; Animals ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/pathology ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Clinical Trials as Topic ; Disease Models, Animal ; Female ; Glioblastoma/drug therapy ; Glioblastoma/pathology ; Humans ; Hydrogels/pharmacology ; Male ; Mice ; Progression-Free Survival ; Spheroids, Cellular/drug effects ; Temozolomide/pharmacology ; Xenograft Model Antitumor Assays
    Chemical Substances Hydrogels ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2019-02-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-18-0359
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  3. Article ; Online: BORIS (CTCFL) is not expressed in most human breast cell lines and high grade breast carcinomas.

    Hines, William C / Bazarov, Alexey V / Mukhopadhyay, Rituparna / Yaswen, Paul

    PloS one

    2010  Volume 5, Issue 3, Page(s) e9738

    Abstract: BORIS (CTCFL) is the only known paralog of the versatile regulatory protein CTCF, a multifunctional DNA binding protein that mediates distinct gene regulatory functions involved in cell growth, differentiation, and apoptosis. Unlike CTCF, the expression ... ...

    Abstract BORIS (CTCFL) is the only known paralog of the versatile regulatory protein CTCF, a multifunctional DNA binding protein that mediates distinct gene regulatory functions involved in cell growth, differentiation, and apoptosis. Unlike CTCF, the expression of BORIS is normally restricted to specific cells in testes (the only cells where CTCF is not expressed), where it may play a role in reprogramming the methylation pattern of male germ line DNA. Frequent amplification of the 20q13.2 region, which contains the BORIS gene, and expression of BORIS transcripts in diverse human tumors and cell lines have led to the hypothesis that aberrant expression of BORIS may play a role in tumorigenesis by interfering with CTCF functions. However, recent studies using more quantitative methods indicate low frequency of BORIS expression in melanoma, ovarian, prostate, and bladder carcinomas. To investigate the relationship between chromosome 20q13 amplification and BORIS mRNA levels within breast cancer cell lines and tissues, we developed a quantitative RT-PCR assay to measure the levels of BORIS mRNA. Endpoint RT-PCR assays were also used to investigate the possible expression of alternatively spliced variants. Using multiple primer sets and controls, we found that neither mature BORIS transcripts nor spliced variants are commonly expressed at detectable levels in malignant breast cells or tissues, although endogenous BORIS transcripts can be induced in MCF-7 cells following 5-aza-2'-deoxycytidine treatment. In conclusion, in most breast cancer cells, endogenous BORIS is unlikely to be expressed at sufficient levels to interfere with CTCF functions. Thus it is improbable that aberrant BORIS expression plays a role in most human breast cancers.
    MeSH term(s) Alternative Splicing ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Breast Neoplasms/metabolism ; CCCTC-Binding Factor ; Carcinoma/metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/biosynthesis ; Decitabine ; Exons ; Fibroblasts/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Polymerase Chain Reaction/methods ; RNA, Messenger/metabolism ; Repressor Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tissue Distribution
    Chemical Substances CCCTC-Binding Factor ; CTCF protein, human ; CTCFL protein, human ; DNA-Binding Proteins ; RNA, Messenger ; Repressor Proteins ; Decitabine (776B62CQ27) ; Azacitidine (M801H13NRU)
    Language English
    Publishing date 2010-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0009738
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The specific role of pRb in p16 (INK4A) -mediated arrest of normal and malignant human breast cells.

    Bazarov, Alexey V / Lee, Won Jae / Bazarov, Irina / Bosire, Moses / Hines, William C / Stankovich, Basha / Chicas, Agustin / Lowe, Scott W / Yaswen, Paul

    Cell cycle (Georgetown, Tex.)

    2012  Volume 11, Issue 5, Page(s) 1008–1013

    Abstract: RB family proteins pRb, p107 and p130 have similar structures and overlapping functions, enabling cell cycle arrest and cellular senescence. pRb, but not p107 or p130, is frequently mutated in human malignancies. In human fibroblasts acutely exposed to ... ...

    Abstract RB family proteins pRb, p107 and p130 have similar structures and overlapping functions, enabling cell cycle arrest and cellular senescence. pRb, but not p107 or p130, is frequently mutated in human malignancies. In human fibroblasts acutely exposed to oncogenic ras, pRb has a specific role in suppressing DNA replication, and p107 or p130 cannot compensate for the loss of this function; however, a second p53/p21-dependent checkpoint prevents escape from growth arrest. This model of oncogene-induced senescence requires the additional loss of p53/p21 to explain selection for preferential loss of pRb function in human malignancies. We asked whether similar rules apply to the role of pRb in growth arrest of human epithelial cells, the source of most cancers. In two malignant human breast cancer cell lines, we found that individual RB family proteins were sufficient for the establishment of p16-initiated senescence, and that growth arrest in G 1 was not dependent on the presence of functional pRb or p53. However, senescence induction by endogenous p16 was delayed in primary normal human mammary epithelial cells with reduced pRb but not with reduced p107 or p130. Thus, under these circumstances, despite the presence of functional p53, p107 and p130 were unable to completely compensate for pRb in mediating senescence induction. We propose that early inactivation of pRb in pre-malignant breast cells can, by itself, extend proliferative lifespan, allowing acquisition of additional changes necessary for malignant transformation.
    MeSH term(s) Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cells, Cultured ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Female ; G1 Phase Cell Cycle Checkpoints ; Humans ; MCF-7 Cells ; RNA Interference ; RNA, Small Interfering/metabolism ; Retinoblastoma Protein/antagonists & inhibitors ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Retinoblastoma-Like Protein p107/antagonists & inhibitors ; Retinoblastoma-Like Protein p107/genetics ; Retinoblastoma-Like Protein p107/metabolism ; Retinoblastoma-Like Protein p130/antagonists & inhibitors ; Retinoblastoma-Like Protein p130/genetics ; Retinoblastoma-Like Protein p130/metabolism ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p16 ; RNA, Small Interfering ; Retinoblastoma Protein ; Retinoblastoma-Like Protein p107 ; Retinoblastoma-Like Protein p130 ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2012-03-01
    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 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.11.5.19492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Cell Labeling with Magneto-Endosymbionts and the Dissection of the Subcellular Location, Fate, and Host Cell Interactions.

    Lee, Kayla R / Wakeel, Abdul / Chakraborty, Papia / Foote, Chandler S / Kajiura, Lauren / Barrozo, Joyce C / Chan, Andrea C / Bazarov, Alexey V / Spitler, Ryan / Kutny, Peter M / Denegre, Jim M / Taft, Rob A / Seemann, Joachim / Rice, Bradley W / Contag, Christopher H / Rutt, Brian K / Bell, Caleb B

    Molecular imaging and biology

    2017  Volume 20, Issue 1, Page(s) 55–64

    Abstract: Purpose: The purposes of this study are to characterize magneto-endosymbiont (ME) labeling of mammalian cells and to discern the subcellular fate of these living contrast agents. MEs are novel magnetic resonance imaging (MRI) contrast agents that are ... ...

    Abstract Purpose: The purposes of this study are to characterize magneto-endosymbiont (ME) labeling of mammalian cells and to discern the subcellular fate of these living contrast agents. MEs are novel magnetic resonance imaging (MRI) contrast agents that are being used for cell tracking studies. Understanding the fate of MEs in host cells is valuable for designing in vivo cell tracking experiments.
    Procedures: The ME's surface epitopes, contrast-producing paramagnetic magnetosomal iron, and genome were studied using immunocytochemistry (ICC), Fe and MRI contrast measurements, and quantitative polymerase chain reaction (qPCR), respectively. These assays, coupled with other common assays, enabled validation of ME cell labeling and dissection of ME subcellular processing.
    Results: The assays mentioned above provide qualitative and quantitative assessments of cell labeling, the subcellular localization and the fate of MEs. ICC results, with an ME-specific antibody, qualitatively shows homogenous labeling with MEs. The ferrozine assay shows that MEs have an average of 7 fg Fe/ME, ∼30 % of which contributes to MRI contrast and ME-labeled MDA-MB-231 (MDA-231) cells generally have 2.4 pg Fe/cell, implying ∼350 MEs/cell. Adjusting the concentration of Fe in the ME growth media reduces the concentration of non-MRI contrast-producing Fe. Results from the qPCR assay, which quantifies ME genomes in labeled cells, shows that processing of MEs begins within 24 h in MDA-231 cells. ICC results suggest this intracellular digestion of MEs occurs by the lysosomal degradation pathway. MEs coated with listeriolysin O (LLO) are able to escape the primary phagosome, but subsequently co-localize with LC3, an autophagy-associated molecule, and are processed for digestion. In embryos, where autophagy is transiently suppressed, MEs show an increased capacity for survival and even replication. Finally, transmission electron microscopy (TEM) of ME-labeled MDA-231 cells confirms that the magnetosomes (the MRI contrast-producing particles) remain intact and enable in vivo cell tracking.
    Conclusions: MEs are used to label mammalian cells for the purpose of cell tracking in vivo, with MRI. Various assays described herein (ICC, ferrozine, and qPCR) allow qualitative and quantitative assessments of labeling efficiency and provide a detailed understanding of subcellular processing of MEs. In some cell types, MEs are digested, but the MRI-producing particles remain. Coating with LLO allows MEs to escape the primary phagosome, enhances retention slightly, and confirms that MEs are ultimately processed by autophagy. Numerous intracellular bacteria and all endosymbiotically derived organelles have evolved molecular mechanisms to avoid intracellular clearance, and identification of the specific processes involved in ME clearance provides a framework on which to develop MEs with enhanced retention in mammalian cells.
    MeSH term(s) Animals ; Autophagy ; Cell Communication ; Cell Line, Tumor ; Cell Tracking ; Contrast Media/chemistry ; Ferrozine/metabolism ; Humans ; Iron/metabolism ; Magnetite Nanoparticles/chemistry ; Magnetite Nanoparticles/ultrastructure ; Mice, Inbred BALB C ; Rats ; Reproducibility of Results ; Staining and Labeling ; Subcellular Fractions/metabolism ; Symbiosis
    Chemical Substances Contrast Media ; Magnetite Nanoparticles ; Ferrozine (28048-33-1) ; Iron (E1UOL152H7)
    Language English
    Publishing date 2017-06-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2079160-4
    ISSN 1860-2002 ; 1536-1632
    ISSN (online) 1860-2002
    ISSN 1536-1632
    DOI 10.1007/s11307-017-1094-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies.

    Mukhopadhyay, Rituparna / Costes, Sylvain V / Bazarov, Alexey V / Hines, William C / Barcellos-Hoff, Mary Helen / Yaswen, Paul

    Breast cancer research : BCR

    2010  Volume 12, Issue 1, Page(s) R11

    Abstract: Introduction: Most human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence ... ...

    Abstract Introduction: Most human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated beta-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16). However, HMEC grown in a serum-free medium, spontaneously yield, at low frequency, variant (v) HMEC that are capable of long-term growth and are susceptible to genomic instability. We investigated whether ionizing radiation, which increases breast cancer risk in women, affects the rate of vHMEC outgrowth.
    Methods: Pre-stasis HMEC cultures were exposed to 5 to 200 cGy of sparsely (X- or gamma-rays) or densely (1 GeV/amu 56Fe) ionizing radiation. Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated beta-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent. Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored. Agent-based modeling, incorporating a simple set of rules and underlying assumptions, was used to simulate vHMEC outgrowth and evaluate mechanistic hypotheses.
    Results: Cultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated beta-galactosidase or p16 expression, than cultures derived from unirradiated cells. As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures. However, the extent of methylation of individual CpG sites in vHMEC samples did not correlate with passage number or treatment. Exposure to sparsely or densely ionizing radiation elicited similar increases in the numbers of vHMEC compared to unirradiated controls. Agent-based modeling indicated that radiation-induced premature senescence of normal HMEC most likely accelerated vHMEC outgrowth through alleviation of spatial constraints. Subsequent experiments using defined co-cultures of vHMEC and senescent cells supported this mechanism.
    Conclusions: Our studies indicate that ionizing radiation can promote the outgrowth of epigenetically altered cells with pre-malignant potential.
    MeSH term(s) Adolescent ; Breast/pathology ; Breast/radiation effects ; Cell Proliferation/radiation effects ; Cells, Cultured ; Dose-Response Relationship, Radiation ; Epithelial Cells/pathology ; Epithelial Cells/radiation effects ; Female ; Gene Silencing ; Genes, p16 ; Humans ; Middle Aged ; Models, Biological
    Language English
    Publishing date 2010-02-10
    Publishing country England
    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 2015059-3
    ISSN 1465-542X ; 1465-5411
    ISSN (online) 1465-542X
    ISSN 1465-5411
    DOI 10.1186/bcr2477
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  7. Article ; Online: Telomerase activation by c-Myc in human mammary epithelial cells requires additional genomic changes.

    Bazarov, Alexey V / Hines, William C / Mukhopadhyay, Rituparna / Beliveau, Alain / Melodyev, Sonya / Zaslavsky, Yuri / Yaswen, Paul

    Cell cycle (Georgetown, Tex.)

    2009  Volume 8, Issue 20, Page(s) 3373–3378

    Abstract: A central question in breast cancer biology is how cancer cells acquire telomerase activity required for unlimited proliferation. According to one model, proliferation of telomerase(-) pre-malignant cells leads to telomere dysfunction and increased ... ...

    Abstract A central question in breast cancer biology is how cancer cells acquire telomerase activity required for unlimited proliferation. According to one model, proliferation of telomerase(-) pre-malignant cells leads to telomere dysfunction and increased genomic instability. Such instability leads in rare cases to reactivation of telomerase and immortalization. The mechanism of telomerase reactivation remains unknown. We have studied immortalization of cultured human mammary epithelial cells by c-Myc, a positive transcriptional regulator of the hTERT gene encoding the catalytic subunit of telomerase. Retrovirally introduced c-Myc cDNA resulted in immortalization of human mammary epithelial cells in which the cyclin dependent kinase inhibitor, p16(INK4A), was inactivated by an shRNA-encoding retrovirus. However, while c-Myc introduction immediately resulted in increased activity of transiently transfected hTERT promoter reporter constructs, endogenous hTERT mRNA levels did not change until about 60 population doublings after c-Myc introduction. Increased endogenous hTERT transcripts and stabilization of telomeric DNA in cells expressing exogenous c-Myc coincided with telomere dysfunction-associated senescence in control cultures. Genome copy number analyses of immortalized cells indicated amplifications of some or all of chromosome 5, where hTERT genes are located. hTERT gene copy number, however, was not increased in one case. The results are consistent with the hypothesis that changes in chromosome 5, while not necessarily increasing hTERT gene copy number, resulted in removal of repressive chromatin structures around hTERT loci, allowing induction of hTERT transcription. These in vitro results model one possible sequence of events leading to immortalization of breast epithelial cells during cancer progression.
    MeSH term(s) Cell Line, Transformed ; Chromosomes, Human, Pair 5 ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Epithelial Cells/enzymology ; Epithelial Cells/metabolism ; Genomic Instability ; Humans ; Mammary Glands, Human/cytology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA Interference ; Telomerase/genetics ; Telomerase/metabolism
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p16 ; Proto-Oncogene Proteins c-myc ; Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2009-10-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.8.20.9856
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  8. Article ; Online: PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.

    Horiuchi, Dai / Camarda, Roman / Zhou, Alicia Y / Yau, Christina / Momcilovic, Olga / Balakrishnan, Sanjeev / Corella, Alexandra N / Eyob, Henok / Kessenbrock, Kai / Lawson, Devon A / Marsh, Lindsey A / Anderton, Brittany N / Rohrberg, Julia / Kunder, Ratika / Bazarov, Alexey V / Yaswen, Paul / McManus, Michael T / Rugo, Hope S / Werb, Zena /
    Goga, Andrei

    Nature medicine

    2016  Volume 22, Issue 11, Page(s) 1321–1329

    Abstract: Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is ... ...

    Abstract Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.
    MeSH term(s) Animals ; Blotting, Western ; Carcinoma, Ductal, Breast/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Female ; Humans ; In Situ Nick-End Labeling ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/genetics ; Mammary Neoplasms, Experimental/metabolism ; Mice, Transgenic ; Microscopy, Fluorescence ; Prognosis ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors ; Proto-Oncogene Proteins c-pim-1/metabolism ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Cdkn1b protein, mouse ; MYC protein, human ; Myc protein, mouse ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-myc ; RNA, Small Interfering ; Receptors, Estrogen ; Receptors, Progesterone ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; PIM1 protein, human (EC 2.7.11.1) ; Pim1 protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1)
    Language English
    Publishing date 2016-10-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/nm.4213
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition.

    Horiuchi, Dai / Kusdra, Leonard / Huskey, Noelle E / Chandriani, Sanjay / Lenburg, Marc E / Gonzalez-Angulo, Ana Maria / Creasman, Katelyn J / Bazarov, Alexey V / Smyth, James W / Davis, Sarah E / Yaswen, Paul / Mills, Gordon B / Esserman, Laura J / Goga, Andrei

    The Journal of experimental medicine

    2012  Volume 209, Issue 4, Page(s) 679–696

    Abstract: Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well ... ...

    Abstract Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors.
    MeSH term(s) Animals ; Apoptosis Regulatory Proteins/analysis ; Apoptosis Regulatory Proteins/physiology ; Bcl-2-Like Protein 11 ; Breast Neoplasms/chemistry ; Breast Neoplasms/drug therapy ; Breast Neoplasms/mortality ; Cell Line, Tumor ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Female ; Humans ; Membrane Proteins/analysis ; Membrane Proteins/physiology ; Mice ; Mice, Inbred BALB C ; Prognosis ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins/physiology ; Proto-Oncogene Proteins c-myc/analysis ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/physiology ; Receptor, ErbB-2/analysis ; Receptors, Estrogen/analysis ; Receptors, Progesterone/analysis ; Signal Transduction/physiology ; Xenograft Model Antitumor Assays
    Chemical Substances Apoptosis Regulatory Proteins ; BCL2L11 protein, human ; Bcl-2-Like Protein 11 ; Bcl2l11 protein, mouse ; MYC protein, human ; Membrane Proteins ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-myc ; Receptors, Estrogen ; Receptors, Progesterone ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2012-03-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20111512
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: p16(INK4a) -mediated suppression of telomerase in normal and malignant human breast cells.

    Bazarov, Alexey V / Van Sluis, Marjolein / Hines, William C / Bassett, Ekaterina / Beliveau, Alain / Campeau, Eric / Mukhopadhyay, Rituparna / Lee, Won Jae / Melodyev, Sonya / Zaslavsky, Yuri / Lee, Leonard / Rodier, Francis / Chicas, Agustin / Lowe, Scott W / Benhattar, Jean / Ren, Bing / Campisi, Judith / Yaswen, Paul

    Aging cell

    2010  Volume 9, Issue 5, Page(s) 736–746

    Abstract: The cyclin-dependent kinase inhibitor p16(INK4a) (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular ... ...

    Abstract The cyclin-dependent kinase inhibitor p16(INK4a) (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal.
    MeSH term(s) Breast/cytology ; Breast/enzymology ; Breast/metabolism ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/enzymology ; Gene Silencing ; Histones/metabolism ; Humans ; Methylation ; Promoter Regions, Genetic/genetics ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Telomerase/antagonists & inhibitors ; Telomerase/genetics ; Telomerase/metabolism
    Chemical Substances Cyclin-Dependent Kinase Inhibitor p16 ; Histones ; RNA, Messenger ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
    Language English
    Publishing date 2010-07-14
    Publishing country England
    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 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/j.1474-9726.2010.00599.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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