Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature o... more Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial‐to‐mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)‐approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, inclu...
Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature o... more Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the MAPK/extracellular signal-regulated kinases (MEK) pathways has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT). Here we proposed to investigate dual inhibition of MEK1/2 and MEK5 as a more efficacious method for intervention to target mesenchymal and highly metastatic breast cancer cells than MEK1/2 or MEK5 alone through the use of a novel pan-MEK inhibitor SC-151. Interestingly, TNBC cells demonstrated a change in cell morphology indicative of mesenchymal-to-epithelial transition (MET) and exhibited a significant decrease in migration potential following pan-MEK inhibition. Additionally, immuno-compromised mice inoculated with MDA-MB-231 cells and treated with SC-151 demonstrated decreased tumor volumes c...
We have previously shown histone deacetylase inhibitor, LBH589 (Panobinostat), to increase E-cadh... more We have previously shown histone deacetylase inhibitor, LBH589 (Panobinostat), to increase E-cadherin expression and alter mesenchymal MDA-MB-231 cell morphology to a more epithelial phenotype suggestive of the reversal of EMT (epithelial-to-mesenchymal transition). As EMT has been linked to enhanced cell motility, we examined the effects of LBH589 on breast cancer cells in vitro. Electrical Cell-substrate Impedance Sensing (ECIS) allows for real-time, noninvasive measurement of cell behavior and reproducible wounding by lethal electroporation of the cell monolayer for migration studies. Method: A 1 uA, 4kHz AC current applied across surface electrodes (250-μm diameter) provided electrical impedance monitoring capability, as MBA-MB-231 or MCF-7 breast cancer cells attached, spread, proliferate on the substrate. Measurements were reported as calculated resistance and capacitance. As cells grow on the substrate, the cell-electrode interaction is such that the current is forced to flow...
Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature o... more Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial‐to‐mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)‐approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, inclu...
Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature o... more Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the MAPK/extracellular signal-regulated kinases (MEK) pathways has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT). Here we proposed to investigate dual inhibition of MEK1/2 and MEK5 as a more efficacious method for intervention to target mesenchymal and highly metastatic breast cancer cells than MEK1/2 or MEK5 alone through the use of a novel pan-MEK inhibitor SC-151. Interestingly, TNBC cells demonstrated a change in cell morphology indicative of mesenchymal-to-epithelial transition (MET) and exhibited a significant decrease in migration potential following pan-MEK inhibition. Additionally, immuno-compromised mice inoculated with MDA-MB-231 cells and treated with SC-151 demonstrated decreased tumor volumes c...
We have previously shown histone deacetylase inhibitor, LBH589 (Panobinostat), to increase E-cadh... more We have previously shown histone deacetylase inhibitor, LBH589 (Panobinostat), to increase E-cadherin expression and alter mesenchymal MDA-MB-231 cell morphology to a more epithelial phenotype suggestive of the reversal of EMT (epithelial-to-mesenchymal transition). As EMT has been linked to enhanced cell motility, we examined the effects of LBH589 on breast cancer cells in vitro. Electrical Cell-substrate Impedance Sensing (ECIS) allows for real-time, noninvasive measurement of cell behavior and reproducible wounding by lethal electroporation of the cell monolayer for migration studies. Method: A 1 uA, 4kHz AC current applied across surface electrodes (250-μm diameter) provided electrical impedance monitoring capability, as MBA-MB-231 or MCF-7 breast cancer cells attached, spread, proliferate on the substrate. Measurements were reported as calculated resistance and capacitance. As cells grow on the substrate, the cell-electrode interaction is such that the current is forced to flow...
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Papers by Matthew Burow