6 results on '"Burow ME"'
Search Results
2. Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor.
- Author
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Chang TC, Matossian MD, Elliott S, Burks HE, Sabol RA, Ucar DA, Wathieu H, Zabaleta J, Del Valle L, Gill S, Martin E, Riker AI, Miele L, Bunnell BA, Burow ME, and Collins-Burow BM
- Subjects
- Animals, Breast Neoplasms genetics, Cell Cycle Proteins genetics, Cell Line, Tumor, Cell Movement drug effects, Cell Survival drug effects, Depsipeptides pharmacology, Drug Synergism, Epithelial-Mesenchymal Transition drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Histone Deacetylase Inhibitors pharmacology, Humans, Lung Neoplasms genetics, Mice, Middle Aged, Neoplastic Cells, Circulating drug effects, Panobinostat pharmacology, Patient-Specific Modeling, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Breast Neoplasms drug therapy, Depsipeptides administration & dosage, Histone Deacetylase Inhibitors administration & dosage, Lung Neoplasms drug therapy, Lung Neoplasms secondary, Panobinostat administration & dosage
- Abstract
Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due to rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers. We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass. DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC. This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
- Full Text
- View/download PDF
3. Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes.
- Author
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Matossian MD, Elliott S, Hoang VT, Burks HE, Phamduy TB, Chrisey DB, Zuercher WJ, Drewry DH, Wells C, Collins-Burow B, and Burow ME
- Subjects
- Animals, Cell Line, Tumor, Cell Movement drug effects, Cell Transdifferentiation drug effects, Drug Screening Assays, Antitumor, Epithelial Cells drug effects, Epithelial Cells pathology, Humans, Mesoderm drug effects, Mesoderm pathology, Mice, Phenotype, Protein Kinase Inhibitors therapeutic use, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Triple Negative Breast Neoplasms enzymology, Triple Negative Breast Neoplasms pathology, Xenograft Model Antitumor Assays, Molecular Targeted Therapy, Protein Kinase Inhibitors pharmacology, Triple Negative Breast Neoplasms drug therapy
- Abstract
Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds' effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype.
- Published
- 2017
- Full Text
- View/download PDF
4. MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis.
- Author
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Antoon JW, Martin EC, Lai R, Salvo VA, Tang Y, Nitzchke AM, Elliott S, Nam SY, Xiong W, Rhodes LV, Collins-Burow B, David O, Wang G, Shan B, Beckman BS, Nephew KP, and Burow ME
- Subjects
- Animals, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinogenesis genetics, Carcinogenesis metabolism, Carcinogenesis pathology, Carcinoma metabolism, Carcinoma pathology, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Epithelial-Mesenchymal Transition genetics, Estradiol analogs & derivatives, Estradiol pharmacology, Estrogen Receptor alpha metabolism, Estrogens metabolism, Female, Fulvestrant, Gene Expression Profiling, Humans, MAP Kinase Kinase 5 metabolism, Mice, Mitogen-Activated Protein Kinase 7 antagonists & inhibitors, Mitogen-Activated Protein Kinase 7 metabolism, Neoplasms, Experimental, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Breast Neoplasms genetics, Carcinoma genetics, Estrogen Receptor alpha genetics, Gene Expression Regulation, Neoplastic, MAP Kinase Kinase 5 genetics, Mitogen-Activated Protein Kinase 7 genetics
- Abstract
Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(-), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.
- Published
- 2013
- Full Text
- View/download PDF
5. Endocrine disruptor regulation of microRNA expression in breast carcinoma cells.
- Author
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Tilghman SL, Bratton MR, Segar HC, Martin EC, Rhodes LV, Li M, McLachlan JA, Wiese TE, Nephew KP, and Burow ME
- Subjects
- Benzhydryl Compounds, Breast Neoplasms genetics, Cell Line, Tumor, Estrogen Receptor alpha metabolism, Estrogens metabolism, Humans, Transcription, Genetic drug effects, Transcriptome drug effects, Breast Neoplasms pathology, DDT pharmacology, Endocrine Disruptors pharmacology, Gene Expression Regulation, Neoplastic drug effects, MicroRNAs genetics, Phenols pharmacology
- Abstract
Background: Several environmental agents termed "endocrine disrupting compounds" or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs). Of the ncRNAs, microRNAs have emerged as a target of estrogen signaling. Given the important implications of EDC-regulated ER function, we sought to define the effects of BPA and DDT on microRNA regulation and expression levels in estrogen-responsive human breast cancer cells., Methodology/principal Findings: To investigate the cellular effects of DDT and BPA, we used the human MCF-7 breast cancer cell line, which is ER (+) and hormone sensitive. Our results show that DDT and BPA potentiate ER transcriptional activity, resulting in an increased expression of receptor target genes, including progesterone receptor, bcl-2, and trefoil factor 1. Interestingly, a differential increase in expression of Jun and Fas by BPA but not DDT or estrogen was observed. In addition to ER responsive mRNAs, we investigated the ability of DDT and BPA to alter the miRNA profiles in MCF-7 cells. While the EDCs and estrogen similarly altered the expression of multiple microRNAs in MCF-7 cells, including miR-21, differential patterns of microRNA expression were induced by DDT and BPA compared to estrogen., Conclusions/significance: We have shown, for the first time, that BPA and DDT, two well known EDCs, alter the expression profiles of microRNA in MCF-7 breast cancer cells. A better understanding of the molecular mechanisms of these compounds could provide important insight into the role of EDCs in human disease, including breast cancer.
- Published
- 2012
- Full Text
- View/download PDF
6. Insulin-like growth factor-1 signaling regulates miRNA expression in MCF-7 breast cancer cell line.
- Author
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Martin EC, Bratton MR, Zhu Y, Rhodes LV, Tilghman SL, Collins-Burow BM, and Burow ME
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma metabolism, Carcinoma pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, Gene Expression Profiling, Humans, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I pharmacology, MicroRNAs metabolism, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases genetics, Mitogen-Activated Protein Kinase Kinases metabolism, Oligonucleotide Array Sequence Analysis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Real-Time Polymerase Chain Reaction, Breast Neoplasms genetics, Carcinoma genetics, Gene Expression Regulation, Neoplastic drug effects, Insulin-Like Growth Factor I metabolism, MicroRNAs genetics, Signal Transduction drug effects
- Abstract
In breast carcinomas, increased levels of insulin-like growth factor 1 (IGF-1) can act as a mitogen to augment tumorigenesis through the regulation of MAPK and AKT signaling pathways. Signaling through these two pathways allows IGF-1 to employ mechanisms that favor proliferation and cellular survival. Here we demonstrate a subset of previously described tumor suppressor and oncogenic microRNAs (miRNAs) that are under the direct regulation of IGF-1 signaling. Additionally, we show that the selective inhibition of either the MAPK or AKT pathways prior to IGF-1 stimulation prevents the expression of previously described tumor suppressor miRNAs that are family and cluster specific. Here we have defined, for the first time, specific miRNAs under the direct regulation of IGF-1 signaling in the estrogen receptor positive MCF-7 breast cancer cell line and demonstrate kinase signaling as a modulator of expression for a small subset of microRNAs. Taken together, these data give new insights into mechanisms governing IGF-1 signaling in breast cancer.
- Published
- 2012
- Full Text
- View/download PDF
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