TY - JOUR
T1 - ROS-induced epithelial-mesenchymal transition in mammary epithelial cells is mediated by NF-κB-dependent activation of Snail
AU - Cichon, Magdalena A.
AU - Radisky, Derek C.
PY - 2014
Y1 - 2014
N2 - Epithelial-mesenchymal transition (EMT) is characterized by loss of cell-cell junctions, polarity and epithelial markers, and in turn, acquisition of mesenchymal features and motility. Changes associated with this developmental process have been extensively implicated in breast cancer progression and metastasis. Matrix metalloproteinases (MMPs) have been identified as specific inducers of EMT in mammary epithelial cells. MMP-3 induces EMT associated with malignant transformation via a pathway dependent upon production of reactive oxygen species (ROS). While the process by which exposure to MMP-3 leads to induction of ROS has been extensively studied, exactly how the MMP-3-induced ROS stimulate EMT remains unknown. Here, we used profiling methods to identify MMP-3-induced transcriptional alterations in mouse mammary epithelial cells, finding common overlap with changes mediated by nuclear factor-κB (NF-κB) and found in advanced breast cancer. In cultured cells, we found that Snail, an ROS-dependent key mediator of MMP-3-induced changes, is regulated by NF-κB in response to MMP-3. More specifically, we found MMP-3 to cause binding of p65 and cRel NF-κB subunits to the Snail promoter, leading to its transcription. Our results identify a specific pathway by which MMPs induce EMT and malignant characteristics, and provide insight into potential therapeutic approaches to target MMP-associated breast cancers.
AB - Epithelial-mesenchymal transition (EMT) is characterized by loss of cell-cell junctions, polarity and epithelial markers, and in turn, acquisition of mesenchymal features and motility. Changes associated with this developmental process have been extensively implicated in breast cancer progression and metastasis. Matrix metalloproteinases (MMPs) have been identified as specific inducers of EMT in mammary epithelial cells. MMP-3 induces EMT associated with malignant transformation via a pathway dependent upon production of reactive oxygen species (ROS). While the process by which exposure to MMP-3 leads to induction of ROS has been extensively studied, exactly how the MMP-3-induced ROS stimulate EMT remains unknown. Here, we used profiling methods to identify MMP-3-induced transcriptional alterations in mouse mammary epithelial cells, finding common overlap with changes mediated by nuclear factor-κB (NF-κB) and found in advanced breast cancer. In cultured cells, we found that Snail, an ROS-dependent key mediator of MMP-3-induced changes, is regulated by NF-κB in response to MMP-3. More specifically, we found MMP-3 to cause binding of p65 and cRel NF-κB subunits to the Snail promoter, leading to its transcription. Our results identify a specific pathway by which MMPs induce EMT and malignant characteristics, and provide insight into potential therapeutic approaches to target MMP-associated breast cancers.
KW - Breast cancer
KW - Epithelial-mesenchymal transition
KW - Matrix metalloproteinase-3
KW - Nuclear factor-κB
KW - Reactive oxygen species
KW - Snail
UR - http://www.scopus.com/inward/record.url?scp=84901218391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901218391&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.1940
DO - 10.18632/oncotarget.1940
M3 - Article
C2 - 24811539
AN - SCOPUS:84901218391
SN - 1949-2553
VL - 5
SP - 2827
EP - 2838
JO - Oncotarget
JF - Oncotarget
IS - 9
ER -