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  1. Article ; Online: Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases.

    Sirkisoon, Sherona R / Wong, Grace L / Aguayo, Noah R / Doheny, Daniel L / Zhu, Dongqin / Regua, Angelina T / Arrigo, Austin / Manore, Sara G / Wagner, Calvin / Thomas, Alexandra / Singh, Ravi / Xing, Fei / Jin, Guangxu / Watabe, Kounosuke / Lo, Hui-Wen

    Cancer letters

    2022  Volume 540, Page(s) 215726

    Abstract: Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, ... ...

    Abstract Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, strongly activated astrocytes. EV-derived microRNA/miRNA microarray revealed tGLI1-positive breast cancer cells highly secreted miR-1290 and miR-1246 encapsulated in EVs. Genetic knockin/knockout studies established a direct link between tGLI1 and both miRNAs. Datamining and analysis of patient samples revealed that BCBM patients had more circulating EV-miRs-1290/1246 than those without metastasis. Ectopic expression of miR-1290 or miR-1246 strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-1290- or miR-1246-overexpressing astrocytes promoted mammospheres. Furthermore, miRs-1290/1246 suppressed expression of FOXA2 transcription repressor, leading to CNTF cytokine secretion and subsequent activation of astrocytes. Finally, we conducted a mouse study to demonstrate that astrocytes overexpressing miR-1290, but not miR-1246, enhanced intracranial colonization and growth of breast cancer cells. Collectively, our findings demonstrate, for the first time, that breast cancer EV-derived miR-1290 and miR-1246 activate astrocytes in the brain metastatic microenvironment and that EV-derived miR-1290 promotes progression of brain metastases through the novel EV-miR-1290→FOXA2→CNTF signaling axis.
    MeSH term(s) Animals ; Astrocytes/metabolism ; Brain/pathology ; Brain Neoplasms/secondary ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Ciliary Neurotrophic Factor/metabolism ; Extracellular Vesicles/metabolism ; Female ; Hepatocyte Nuclear Factor 3-beta/genetics ; Hepatocyte Nuclear Factor 3-beta/metabolism ; Humans ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Transcription Factors/metabolism ; Tumor Microenvironment
    Chemical Substances Ciliary Neurotrophic Factor ; FOXA2 protein, human ; MIRN1290 microRNA, human ; MicroRNAs ; Transcription Factors ; Hepatocyte Nuclear Factor 3-beta (135845-92-0)
    Language English
    Publishing date 2022-05-16
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2022.215726
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1177: Show issues Location:
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  2. Article: An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1.

    Doheny, Daniel / Manore, Sara / Sirkisoon, Sherona R / Zhu, Dongqin / Aguayo, Noah R / Harrison, Alexandria / Najjar, Mariana / Anguelov, Marlyn / Cox, Anderson O'Brien / Furdui, Cristina M / Watabe, Kounosuke / Hollis, Thomas / Thomas, Alexandra / Strowd, Roy / Lo, Hui-Wen

    Cancers

    2022  Volume 14, Issue 17

    Abstract: The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. ...

    Abstract The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes
    Language English
    Publishing date 2022-08-31
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14174256
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers.

    Regua, Angelina T / Aguayo, Noah R / Jalboush, Sara Abu / Doheny, Daniel L / Manore, Sara G / Zhu, Dongqin / Wong, Grace L / Arrigo, Austin / Wagner, Calvin J / Yu, Yang / Thomas, Alexandra / Chan, Michael D / Ruiz, Jimmy / Jin, Guangxu / Strowd, Roy / Sun, Peiqing / Lin, Jiayuh / Lo, Hui-Wen

    Cancers

    2021  Volume 13, Issue 10

    Abstract: JAK2-STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that ... ...

    Abstract JAK2-STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining-confocal microscopy and immunoprecipitation-Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA-STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA-STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes,
    Language English
    Publishing date 2021-05-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13102340
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Correction: TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment.

    Sirkisoon, Sherona R / Carpenter, Richard L / Rimkus, Tadas / Doheny, Daniel / Zhu, Dongqin / Aguayo, Noah R / Xing, Fei / Chan, Michael / Ruiz, Jimmy / Metheny-Barlow, Linda J / Strowd, Roy / Lin, Jiayuh / Regua, Angelina T / Arrigo, Austin / Anguelov, Marlyn / Pasche, Boris / Debinski, Waldemar / Watabe, Kounosuke / Lo, Hui-Wen

    Oncogene

    2021  Volume 40, Issue 12, Page(s) 2338

    Language English
    Publishing date 2021-03-02
    Publishing country England
    Document type Published Erratum
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-020-01620-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2218: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  5. Article ; Online: TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment.

    Sirkisoon, Sherona R / Carpenter, Richard L / Rimkus, Tadas / Doheny, Daniel / Zhu, Dongqin / Aguayo, Noah R / Xing, Fei / Chan, Michael / Ruiz, Jimmy / Metheny-Barlow, Linda J / Strowd, Roy / Lin, Jiayuh / Regua, Angelina T / Arrigo, Austin / Anguelov, Marlyn / Pasche, Boris / Debinski, Waldemar / Watabe, Kounosuke / Lo, Hui-Wen

    Oncogene

    2019  Volume 39, Issue 1, Page(s) 64–78

    Abstract: Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never ...

    Abstract Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.
    MeSH term(s) Animals ; Astrocytes/metabolism ; Astrocytes/pathology ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/secondary ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Breast Neoplasms/radiotherapy ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Heterografts ; Humans ; Hyaluronan Receptors/genetics ; Lymphatic Metastasis ; Mice ; Nanog Homeobox Protein/genetics ; Neoplastic Stem Cells/pathology ; Neoplastic Stem Cells/radiation effects ; Octamer Transcription Factor-3/genetics ; Receptor, ErbB-2/genetics ; SOXB1 Transcription Factors/genetics ; Transcription Factors/genetics ; Tumor Microenvironment/genetics ; Zinc Finger Protein GLI1/genetics ; Zinc Finger Protein GLI1/metabolism
    Chemical Substances GLI1 protein, human ; Hyaluronan Receptors ; NANOG protein, human ; Nanog Homeobox Protein ; Octamer Transcription Factor-3 ; POU5F1 protein, human ; SOX2 protein, human ; SOXB1 Transcription Factors ; Transcription Factors ; Zinc Finger Protein GLI1 ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2019-08-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-019-0959-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2218: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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    ab Jg. 2022: Lesesaal (EG)

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