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

110 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

Cite this

Lim, Yat Yuen ; Wright, Josephine ; Attema, Joanne L. ; Gregory, Philip A. ; Bert, Andrew G. ; Smith, Eric ; Thomas, Daniel ; Lopez, Angel F. ; Drew, Paul A. ; Khew-Goodall, Yeesim ; Goodall, Gregory J. / Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-celllike state. In: Journal of Cell Science. 2013 ; Vol. 126, No. 10. pp. 2256-2266.
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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.",
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Lim, YY, Wright, J, Attema, JL, Gregory, PA, Bert, AG, Smith, E, Thomas, D, Lopez, AF, Drew, PA, Khew-Goodall, Y & Goodall, GJ 2013, 'Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-celllike state', Journal of Cell Science, vol. 126, no. 10, pp. 2256-2266. https://doi.org/10.1242/jcs.122275

Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-celllike state. / Lim, Yat Yuen; Wright, Josephine; Attema, Joanne L.; Gregory, Philip A.; Bert, Andrew G.; Smith, Eric; Thomas, Daniel; Lopez, Angel F.; Drew, Paul A.; Khew-Goodall, Yeesim; Goodall, Gregory J.

In: Journal of Cell Science, Vol. 126, No. 10, 01.05.2013, p. 2256-2266.

Research output: Contribution to journalArticle

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AU - Lim, Yat Yuen

AU - Wright, Josephine

AU - Attema, Joanne L.

AU - Gregory, Philip A.

AU - Bert, Andrew G.

AU - Smith, Eric

AU - Thomas, Daniel

AU - Lopez, Angel F.

AU - Drew, Paul A.

AU - Khew-Goodall, Yeesim

AU - Goodall, Gregory J.

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N2 - 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.

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