title: MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis.
abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and lacks effective targeted therapies. The microRNA-200 (miR-200) family is found to inhibit or promote breast cancer metastasis; however, the underlying mechanism is not well understood. This study was performed to investigate the effect and mechanism of miR-200b on TNBC metastasis and identify targets for developing more efficient treatment for TNBC. We found that miR-200 family expression levels are significantly lower in highly migratory TNBC cells and metastatic TNBC tumors than other types of breast cancer cells and tumors. Ectopically expressing a single member (miR-200b) of the miR-200 family drastically reduces TNBC cell migration and inhibits tumor metastasis in an orthotopic mouse mammary xenograft tumor model. We identified protein kinase Cα (PKCα) as a new direct target of miR-200b and found that PKCα protein levels are inversely correlated with miR-200b levels in 12 kinds of breast cancer cells. Inhibiting PKCα activity or knocking down PKCα levels significantly reduces TNBC cell migration. In contrast, forced expression of PKCα impairs the inhibitory effect of miR-200b on cell migration and tumor metastasis. Further mechanistic studies revealed that PKCα downregulation by miR-200b results in a significant decrease of Rac1 activation in TNBC cells. These results show that loss of miR-200b expression plays a crucial role in TNBC aggressiveness and that miR-200b suppresses TNBC cell migration and tumor metastasis by targeting PKCα. Our findings suggest that miR-200b and PKCα may serve as promising therapeutic targets for metastatic TNBC.
authors.affiliation: Department of Physiology and Cellular and Molecular Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Brock
authors.initials: B
authors.lastname: Humphries
authors.affiliation: Department of Physiology and.
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Physiology and.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Oom
authors.affiliation: Department of Physiology and.
authors.forename: Theresa
authors.initials: T
authors.lastname: Fisher
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Tan
authors.affiliation: Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, Guangdong 510182, People's Republic of China and.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Cellular and Molecular Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA yangcf@msu.edu.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C107953:RAC1 protein, human; D051571:Protein Kinase C-alpha; D020830:rac1 GTP-Binding Protein