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  1. AU="Pitner, Mary Kathryn"
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  3. AU="Diana Farah"
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  5. AU=Fiedler S
  6. AU="Grzegorz Zaguła"
  7. AU="Ong, Pio"
  8. AU="Fefelova, Elena A"
  9. AU=Hamid Husnain
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  1. Artikel ; Online: Correction: Maternal Embryonic Leucine Zipper Kinase Is Associated with Metastasis in Triple-negative Breast Cancer.

    Xie, Xuemei / Chauhan, Gaurav B / Edupuganti, Ramakrishna / Kogawa, Takahiro / Park, Jihyun / Tacam, Moises / Tan, Alex W / Mughees, Mohd / Vidhu, Fnu / Liu, Diane D / Taliaferro, Juliana M / Pitner, Mary Kathryn / Browning, Luke S / Lee, Ju-Hyeon / Bertucci, François / Shen, Yu / Wang, Jian / Ueno, Naoto T / Krishnamurthy, Savitri /
    Hortobagyi, Gabriel N / Tripathy, Debu / Van Laere, Steven J / Bartholomeusz, Geoffrey / Dalby, Kevin N / Bartholomeusz, Chandra

    Cancer research communications

    2024  Band 4, Heft 1, Seite(n) 236

    Sprache Englisch
    Erscheinungsdatum 2024-01-28
    Erscheinungsland United States
    Dokumenttyp Published Erratum
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.CRC-24-0046
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: MELK: a potential novel therapeutic target for TNBC and other aggressive malignancies.

    Pitner, Mary Kathryn / Taliaferro, Juliana M / Dalby, Kevin N / Bartholomeusz, Chandra

    Expert opinion on therapeutic targets

    2017  Band 21, Heft 9, Seite(n) 849–859

    Abstract: Introduction: There is an unmet need in triple-negative breast cancer (TNBC) patients for targeted therapies. Maternal embryonic leucine zipper kinase (MELK) is a promising target for inhibition based on the abundance of correlative and functional data ... ...

    Abstract Introduction: There is an unmet need in triple-negative breast cancer (TNBC) patients for targeted therapies. Maternal embryonic leucine zipper kinase (MELK) is a promising target for inhibition based on the abundance of correlative and functional data supporting its role in various cancer types. Areas covered: This review endeavors to outline the role of MELK in cancer. Studies covering a range of biological functions including proliferation, apoptosis, cancer stem cell phenotypes, epithelial-to-mesenchymal transition, metastasis, and therapy resistance are discussed here in order to understand the potential of MELK as a clinically significant target for TNBC patients. Expert opinion: Targeting MELK may offer a novel therapeutic opportunity in TNBC and other cancers. Despite the abundance of correlative data, there is still much we do not know. There are a lack of potent, specific inhibitors against MELK, as well as an insufficient understanding of MELK's downstream substrates. Addressing these issues is the first step toward identifying a patient population that could benefit from MELK inhibition in combination with other therapies.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Drug Design ; Female ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/pathology ; Neoplastic Stem Cells/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/pathology
    Chemische Substanzen Antineoplastic Agents ; Protein Kinase Inhibitors ; MELK protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2017-09
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2055208-7
    ISSN 1744-7631 ; 1472-8222
    ISSN (online) 1744-7631
    ISSN 1472-8222
    DOI 10.1080/14728222.2017.1363183
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer.

    Xie, Xuemei / Chauhan, Gaurav B / Edupuganti, Ramakrishna / Kogawa, Takahiro / Park, Jihyun / Tacam, Moises / Tan, Alex W / Mughees, Mohd / Vidhu, Fnu / Liu, Diane D / Taliaferro, Juliana M / Pitner, Mary Kathryn / Browning, Luke S / Lee, Ju-Hyeon / Shen, Yu / Wang, Jian / Ueno, Naoto T / Krishnamurthy, Savitri / Hortobagyi, Gabriel N /
    Tripathy, Debu / Van Laere, Steven J / Bartholomeusz, Geoffrey / Dalby, Kevin N / Bartholomeusz, Chandra

    Cancer research communications

    2023  Band 3, Heft 6, Seite(n) 1078–1092

    Abstract: Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase ... ...

    Abstract Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that
    Significance: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.
    Mesh-Begriff(e) Humans ; Animals ; Mice ; Triple Negative Breast Neoplasms/genetics ; Mice, Nude ; Leucine Zippers ; Cell Proliferation/physiology ; Neoplasm Recurrence, Local ; Protein Serine-Threonine Kinases/genetics
    Chemische Substanzen MELK protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Sprache Englisch
    Erscheinungsdatum 2023-06-20
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.CRC-22-0330
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Cdk4 and nek2 signal binucleation and centrosome amplification in a her2+ breast cancer model.

    Harrison Pitner, Mary Kathryn / Saavedra, Harold I

    PloS one

    2013  Band 8, Heft 6, Seite(n) e65971

    Abstract: Centrosome amplification (CA) is a contributor to carcinogenesis, generating aneuploidy, and chromosome instability. Previous work shows that breast adenocarcinomas have a higher frequency of centrosome defects compared to normal breast tissues. Abnormal ...

    Abstract Centrosome amplification (CA) is a contributor to carcinogenesis, generating aneuploidy, and chromosome instability. Previous work shows that breast adenocarcinomas have a higher frequency of centrosome defects compared to normal breast tissues. Abnormal centrosome phenotypes are found in pre-malignant lesions, suggesting an early role in breast carcinogenesis. However, the role of CA in breast cancers remains elusive. Identification of pathways and regulatory molecules involved in the generation of CA is essential to understanding its role in breast tumorigenesis. We established a breast cancer model of CA using Her2-positive cells. Our goal was to identify centrosome cycle molecules that are deregulated by aberrant Her2 signaling and the mechanisms driving CA. Our results show some Her2+ breast cancer cell lines harbor both CA and binucleation. Abolishing the expression of Cdk4 abrogated both CA and binucleation in these cells. We also found the source of binucleation in these cells to be defective cytokinesis that is normalized by downregulation of Cdk4. Protein levels of Nek2 diminish upon Cdk4 knockdown and vice versa, suggesting a molecular connection between Cdk4 and Nek2. Knockdown of Nek2 reduces CA and binucleation in this model while its overexpression further enhances centrosome amplification. We conclude that CA is modulated through Cdk4 and Nek2 signaling and that binucleation is a likely source of CA in Her2+ breast cancer cells.
    Mesh-Begriff(e) Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Centrosome/metabolism ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Lentivirus/genetics ; NIMA-Related Kinases ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Receptor, ErbB-2/metabolism ; S Phase
    Chemische Substanzen Receptor, ErbB-2 (EC 2.7.10.1) ; NEK2 protein, human (EC 2.7.11.1) ; NIMA-Related Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
    Sprache Englisch
    Erscheinungsdatum 2013-06-11
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0065971
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells.

    Battula, Venkata Lokesh / Nguyen, Khoa / Sun, Jeff / Pitner, Mary Kathryn / Yuan, Bin / Bartholomeusz, Chandra / Hail, Numsen / Andreeff, Michael

    Oncotarget

    2017  Band 8, Heft 23, Seite(n) 36936–36949

    Abstract: We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and ... ...

    Abstract We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541-treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function,and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases.
    Sprache Englisch
    Erscheinungsdatum 2017-06-06
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.16294
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Differential functions of ERK1 and ERK2 in lung metastasis processes in triple-negative breast cancer.

    Gagliardi, Maria / Pitner, Mary Kathryn / Park, Jihyun / Xie, Xuemei / Saso, Hitomi / Larson, Richard A / Sammons, Rachel M / Chen, Huiqin / Wei, Caimiao / Masuda, Hiroko / Chauhan, Gaurav / Kondo, Kimie / Tripathy, Debu / Ueno, Naoto T / Dalby, Kevin N / Debeb, Bisrat G / Bartholomeusz, Chandra

    Scientific reports

    2020  Band 10, Heft 1, Seite(n) 8537

    Abstract: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients ... ...

    Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.
    Mesh-Begriff(e) Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Movement ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/secondary ; Mice ; Mice, SCID ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 1/genetics ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 3/genetics ; Mitogen-Activated Protein Kinase 3/metabolism ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Prognosis ; RNA, Small Interfering/genetics ; Survival Rate ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism ; Triple Negative Breast Neoplasms/pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemische Substanzen Biomarkers, Tumor ; RNA, Small Interfering ; MAPK1 protein, human (EC 2.7.11.24) ; MAPK3 protein, human (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24)
    Sprache Englisch
    Erscheinungsdatum 2020-05-22
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-65250-3
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: MEK Inhibitor Selumetinib (AZD6244; ARRY-142886) Prevents Lung Metastasis in a Triple-Negative Breast Cancer Xenograft Model.

    Bartholomeusz, Chandra / Xie, Xuemei / Pitner, Mary Kathryn / Kondo, Kimie / Dadbin, Ali / Lee, Jangsoon / Saso, Hitomi / Smith, Paul D / Dalby, Kevin N / Ueno, Naoto T

    Molecular cancer therapeutics

    2015  Band 14, Heft 12, Seite(n) 2773–2781

    Abstract: Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of ... ...

    Abstract Patients with triple-negative breast cancer (TNBC) have a poor prognosis because TNBC often metastasizes, leading to death. Among patients with TNBC, those with extracellular signal-regulated kinase 2 (ERK2)-overexpressing tumors were at higher risk of death than those with low-ERK2-expressing tumors (hazard ratio, 2.76; 95% confidence interval, 1.19-6.41). The MAPK pathway has been shown to be a marker of breast cancer metastasis, but has not been explored as a potential therapeutic target for preventing TNBC metastasis. Interestingly, when we treated TNBC cells with the allosteric MEK inhibitor selumetinib, cell viability was not reduced in two-dimensional culture. However, in three-dimensional culture, selumetinib changed the mesenchymal phenotype of TNBC cells to an epithelial phenotype. Cells that undergo epithelial-mesenchymal transition (EMT) are thought to contribute to the metastatic process. EMT leads to generation of mesenchymal-like breast cancer cells with stem cell-like characteristics and a CD44(+)CD24(-/low) expression pattern. We tested the hypothesis that targeted inhibition of the MAPK pathway by selumetinib inhibits acquisition of the breast cancer stem cell phenotype and prevents lung metastasis of TNBC. TNBC cells treated with selumetinib showed inhibition of anchorage-independent growth, an indicator of in vivo tumorigenicity (P < 0.005), and decreases in the CD44(+)CD24(-/low) fraction, ALDH1 activity, and mammosphere-forming efficiency. Mice treated with selumetinib formed significantly fewer lung metastases than control mice injected with vehicle (P < 0.05). Our data demonstrate that MEK inhibitors can inhibit breast cancer stem cells and may have clinical potential for the prevention of metastasis in certain cases in which tumors are MAPK dependent.
    Mesh-Begriff(e) Animals ; Apoptosis/drug effects ; Benzimidazoles/administration & dosage ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/secondary ; MAP Kinase Kinase Kinase 1/antagonists & inhibitors ; MAP Kinase Kinase Kinase 1/genetics ; Mice ; Protein Kinase Inhibitors/administration & dosage ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology ; Xenograft Model Antitumor Assays
    Chemische Substanzen AZD 6244 ; Benzimidazoles ; Protein Kinase Inhibitors ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25)
    Sprache Englisch
    Erscheinungsdatum 2015-09-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-15-0243
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Silencing CDK4 radiosensitizes breast cancer cells by promoting apoptosis.

    Hagen, Katie R / Zeng, Xiangbin / Lee, Mi-Young / Tucker Kahn, Shannon / Harrison Pitner, Mary Kathryn / Zaky, Sandra S / Liu, Yuan / O'Regan, Ruth M / Deng, Xingming / Saavedra, Harold I

    Cell division

    2013  Band 8, Heft 1, Seite(n) 10

    Abstract: Background: The discovery of molecular markers associated with various breast cancer subtypes has greatly improved the treatment and outcome of breast cancer patients. Unfortunately, breast cancer cells acquire resistance to various therapies. Mounting ... ...

    Abstract Background: The discovery of molecular markers associated with various breast cancer subtypes has greatly improved the treatment and outcome of breast cancer patients. Unfortunately, breast cancer cells acquire resistance to various therapies. Mounting evidence suggests that resistance is rooted in the deregulation of the G1 phase regulatory machinery.
    Methods: To address whether deregulation of the G1 phase regulatory machinery contributes to radiotherapy resistance, the MCF10A immortalized human mammary epithelial cell line, ER-PR-Her2+ and ER-PR-Her2- breast cancer cell lines were irradiated. Colony formation assays measured radioresistance, while immunocytochemistry, Western blots, and flow cytometry measured the cell cycle, DNA replication, mitosis, apoptosis, and DNA breaks.
    Results: Molecular markers common to all cell lines were overexpressed, including cyclin A1 and cyclin D1, which impinge on CDK2 and CDK4 activities, respectively. We addressed their potential role in radioresistance by generating cell lines stably expressing small hairpin RNAs (shRNA) against CDK2 and CDK4. None of the cell lines knocked down for CDK2 displayed radiosensitization. In contrast, all cell lines knocked down for CDK4 were significantly radiosensitized, and a CDK4/CDK6 inhibitor sensitized MDA-MB-468 to radiation induced apoptosis. Our data showed that silencing CDK4 significantly increases radiation induced cell apoptosis in cell lines without significantly altering cell cycle progression, or DNA repair after irradiation. Our results indicate lower levels of phospho-Bad at ser136 upon CDK4 silencing and ionizing radiation, which has been shown to signal apoptosis.
    Conclusion: Based on our data we conclude that knockdown of CDK4 activity sensitizes breast cancer cells to radiation by activating apoptosis pathways.
    Sprache Englisch
    Erscheinungsdatum 2013-07-25
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 1747-1028
    ISSN 1747-1028
    DOI 10.1186/1747-1028-8-10
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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