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Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state
Yat-Yuen Lim, Josephine A. 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


The miR-200 family is a key regulator of the epithelial–mesenchymal transition, however, its role in controlling the transition between cancer stem-cell-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. Stem-like 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.


  • Author contributions

    Y.-Y.L., J.A.W., J.J.A., P.A.G., D.T., A.F.L., P.A.D., Y.K.-G. and G.J.G. conceived and designed experiments. Y.-Y.L., J.A.W., J.J.A., A.G.B. and E.S. performed experiments and analysed the data. Y.-Y.L., J.A.W., J.J.A., P.A.G., Y.K.-G. and G.J.G. wrote the manuscript.

  • Funding

    This work was supported by a fellowship from the National Cancer Foundation Australia [grant number ECF-09-08 to P.A.G.]; a scholarship from the University of Malaya Skim Latihan Akademik IPTA program [to Y.-Y.L.]; and grants from the National Health and Medical Research Council [grant numbers 626918 and 1008440 to G.J.G. and Y.K.-G.]; and the Cancer Council South Australia [grant number 626956 to G.J.G., Y.K.-G. and P.A.G. and 1005078 to P.A.D.].

  • Supplementary material available online at

  • Accepted February 27, 2013.
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