MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells

Suling Liu, Shivani H. Patel, Christophe Ginestier, Ingrid Ibarra, Rachel Martin-Trevino, Shoumin Bai, Sean P. McDermott, Li Shang, Jia Ke, Sing J. Ou, Amber Heath, Kevin J. Zhang, Hasan Korkaya, Shawn G. Clouthier, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Gregory J. Hannon, Max S. Wicha

Research output: Contribution to journalArticle

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Abstract

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 "claudinlow" 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.

Original languageEnglish (US)
Article numbere1002751
JournalPLoS Genetics
Volume8
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

Neoplastic Stem Cells
breasts
stem cells
cancer
Breast
Stem Cells
stem
MicroRNAs
Heterografts
Down-Regulation
tumor
gene
Breast Neoplasms
Epithelial-Mesenchymal Transition
Mammaplasty
microRNA
MCF-7 Cells
breast neoplasms
Regulator Genes
Tumor Suppressor Genes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Liu, S., Patel, S. H., Ginestier, C., Ibarra, I., Martin-Trevino, R., Bai, S., ... Wicha, M. S. (2012). MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genetics, 8(6), [e1002751]. https://doi.org/10.1371/journal.pgen.1002751

MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. / Liu, Suling; Patel, Shivani H.; Ginestier, Christophe; Ibarra, Ingrid; Martin-Trevino, Rachel; Bai, Shoumin; McDermott, Sean P.; Shang, Li; Ke, Jia; Ou, Sing J.; Heath, Amber; Zhang, Kevin J.; Korkaya, Hasan; Clouthier, Shawn G.; Charafe-Jauffret, Emmanuelle; Birnbaum, Daniel; Hannon, Gregory J.; Wicha, Max S.

In: PLoS Genetics, Vol. 8, No. 6, e1002751, 01.06.2012.

Research output: Contribution to journalArticle

Liu, S, Patel, SH, Ginestier, C, Ibarra, I, Martin-Trevino, R, Bai, S, McDermott, SP, Shang, L, Ke, J, Ou, SJ, Heath, A, Zhang, KJ, Korkaya, H, Clouthier, SG, Charafe-Jauffret, E, Birnbaum, D, Hannon, GJ & Wicha, MS 2012, 'MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells', PLoS Genetics, vol. 8, no. 6, e1002751. https://doi.org/10.1371/journal.pgen.1002751
Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S et al. MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genetics. 2012 Jun 1;8(6). e1002751. https://doi.org/10.1371/journal.pgen.1002751
Liu, Suling ; Patel, Shivani H. ; Ginestier, Christophe ; Ibarra, Ingrid ; Martin-Trevino, Rachel ; Bai, Shoumin ; McDermott, Sean P. ; Shang, Li ; Ke, Jia ; Ou, Sing J. ; Heath, Amber ; Zhang, Kevin J. ; Korkaya, Hasan ; Clouthier, Shawn G. ; Charafe-Jauffret, Emmanuelle ; Birnbaum, Daniel ; Hannon, Gregory J. ; Wicha, Max S. / MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. In: PLoS Genetics. 2012 ; Vol. 8, No. 6.
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