Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4

Oncogene. 2013 May 16;32(20):2555-64. doi: 10.1038/onc.2012.275. Epub 2012 Jul 2.


The female hormone progesterone (P4) promotes the expansion of stem-like cancer cells in estrogen receptor (ER)- and progesterone receptor (PR)-positive breast tumors. The expanded tumor cells lose expression of ER and PR, express the tumor-initiating marker CD44, the progenitor marker cytokeratin 5 (CK5) and are more resistant to standard endocrine and chemotherapies. The mechanisms underlying this hormone-stimulated reprogramming have remained largely unknown. In the present study, we investigated the role of microRNAs in progestin-mediated expansion of this dedifferentiated tumor cell population. We demonstrate that P4 rapidly downregulates miR-29 family members, particularly in the CD44(+) cell population. Downregulation of miR-29 members potentiates the expansion of CK5(+) and CD44(+) cells in response to progestins, and results in increased stem-like properties in vitro and in vivo. We demonstrate that miR-29 directly targets Krüppel-like factor 4 (KLF4), a transcription factor required for the reprogramming of differentiated cells to pluripotent stem cells, and for the maintenance of breast cancer stem cells. These results reveal a novel mechanism, whereby progestins increase the stem cell-like population in hormone-responsive breast cancers, by decreasing miR-29 to augment PR-mediated upregulation of KLF4. Elucidating the mechanisms whereby hormones mediate the expansion of stem-like cells furthers our understanding of the progression of hormone-responsive breast cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hyaluronan Receptors / metabolism
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, SCID
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Progesterone / pharmacology
  • Progestins / pharmacology*
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • 3' Untranslated Regions
  • CD44 protein, human
  • Hyaluronan Receptors
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • MIRN29a microRNA, human
  • MicroRNAs
  • Progestins
  • Progesterone