Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential.
Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of known EMT regulators, miR-200 family of microRNAs in controlling the epithelial state, stem-like properties and therapeutic response in an in vivo primary, syngeneic p53(null) claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. miR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion and motility. Accordingly, induced miR200c expression significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53(null) claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity and metastatic potential in vivo.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
J
J
Knezevic
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
A D
AD
Pfefferle
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
I
I
Petrovic
Epic Sciences, Inc., San Diego, CA, USA.
S B
SB
Greene
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.|Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
C M
CM
Perou
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
J M
JM
Rosen
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology
D057167:Claudins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin; D016190:Carboplatin