Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells.
Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells.
Shimono
Yohei
Y
Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304, USA.
Zabala
Maider
M
Cho
Robert W
RW
Lobo
Neethan
N
Dalerba
Piero
P
Qian
Dalong
D
Diehn
Maximilian
M
Liu
Huiping
H
Panula
Sarita P
SP
Chiao
Eric
E
Dirbas
Frederick M
FM
Somlo
George
G
Pera
Renee A Reijo
RA
Lao
Kaiqin
K
Clarke
Michael F
MF
D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
C069077:BMI1 protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1