MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells.
MicroRNAs (miRNAs) play important roles in normal cellular differentiation and oncogenesis. microRNA93 (mir-93), a member of the mir106b-25 cluster, located in intron 13 of the MCM7 gene, although frequently overexpressed in human malignancies may also function as a tumor suppressor gene. Using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, we demonstrate that mir-93 modulates the fate of breast cancer stem cells (BCSCs) by regulating their proliferation and differentiation states. In "claudin(low)" SUM159 cells, expression of mir-93 induces Mesenchymal-Epithelial Transition (MET) associated with downregulation of TGFβ signaling and downregulates multiple stem cell regulatory genes, including JAK1, STAT3, AKT3, SOX4, EZH1, and HMGA2, resulting in cancer stem cell (CSC) depletion. Enforced expression of mir-93 completely blocks tumor development in mammary fat pads and development of metastases following intracardiac injection in mouse xenografts. The effect of mir-93 on the CSC population is dependent on the cellular differentiation state, with mir-93 expression increasing the CSC population in MCF7 cells that display a more differentiated "luminal" phenotype. mir-93 also regulates the proliferation and differentiation of normal breast stem cells isolated from reduction mammoplasties. These studies demonstrate that miRNAs can regulate the states and fates of normal and malignant mammary stem cells, findings which have important biological and clinical implications.
Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. sulingl@med.umich.edu
Suling
S
Liu
Shivani H
SH
Patel
Christophe
C
Ginestier
Ingrid
I
Ibarra
Rachel
R
Martin-Trevino
Shoumin
S
Bai
Sean P
SP
McDermott
Li
L
Shang
Jia
J
Ke
Sing J
SJ
Ou
Amber
A
Heath
Kevin J
KJ
Zhang
Hasan
H
Korkaya
Shawn G
SG
Clouthier
Emmanuelle
E
Charafe-Jauffret
Daniel
D
Birnbaum
Gregory J
GJ
Hannon
Max S
MS
Wicha
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D064168:Minichromosome Maintenance Complex Component 7; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7