Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/79622
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Type: Journal article
Title: Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state
Author: Lim, Y.
Wright, J.
Attema, J.
Gregory, P.
Bert, A.
Smith, E.
Thomas, D.
Lopez, A.
Drew, P.
Khew-Goodall, Y.
Goodall, G.
Citation: Journal of Cell Science, 2013; 126(10):2256-2266
Publisher: Company of Biologists Ltd
Issue Date: 2013
ISSN: 0021-9533
1477-9137
Statement of
Responsibility: 
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 and Gregory J. Goodall
Abstract: 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.
Keywords: Epithelial-mesenchymal transition
breast cancer stem cells
miR-200
DNA methylation
histone modifications
gene regulation
Rights: © The Company of Biologists Ltd 2013
DOI: 10.1242/jcs.122275
Grant ID: http://purl.org/au-research/grants/nhmrc/626918
http://purl.org/au-research/grants/nhmrc/1008440
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