Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-celllike state

Yat Yuen Lim, Josephine Wright, Joanne L. Attema, Philip A. Gregory, Andrew G. Bert, Eric Smith, Daniel Thomas, Angel F. Lopez, Paul A. Drew, Yeesim Khew-Goodall, Gregory J. Goodall

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

The miR-200 family is a key regulator of the epithelial-mesenchymal transition, however, its role in controlling the transition between cancer stemcell- like and non-stem-cell-like phenotypes is not well understood. We utilized immortalized human mammary epithelial (HMLE) cells to investigate the regulation of the miR-200 family during their conversion to a stem-like phenotype. HMLE cells were found to be capable of spontaneous conversion from a non-stem to a stem-like phenotype and this conversion was accompanied by the loss of miR-200 expression. Stemlike cell fractions isolated from metastatic breast cancers also displayed loss of miR-200 indicating similar molecular changes may occur during breast cancer progression. The phenotypic change observed in HMLE cells was directly controlled by miR-200 because restoration of its expression decreased stem-like properties while promoting a transition to an epithelial phenotype. Investigation of the mechanisms controlling miR-200 expression revealed both DNA methylation and histone modifications were significantly altered in the stem-like and non-stem phenotypes. In particular, in the stem-like phenotype, the miR-200b-200a-429 cluster was silenced primarily through polycomb group-mediated histone modifications whereas the miR-200c-141 cluster was repressed by DNA methylation. These results indicate that the miR-200 family plays a crucial role in the transition between stem-like and non-stem phenotypes and that distinct epigenetic-based mechanisms regulate each miR-200 gene in this process. Therapy targeted against miR-200 family members and epigenetic modifications might therefore be applicable to breast cancer.

LanguageEnglish
Pages2256-2266
Number of pages11
JournalJournal of Cell Science
Volume126
Issue number10
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Breast cancer stem cells
  • DNA methylation
  • Epithelial-mesenchymal transition
  • Gene regulation
  • Histone modifications
  • MiR-200

ASJC Scopus subject areas

  • Cell Biology

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