title: Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4.
abstract: 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.
authors: Department of Pathology, University of Colorado Denver, Aurora, CO 80045, USA.
authors: D M
authors: DM
authors: Cittelly
authors: J
authors: J
authors: Finlay-Schultz
authors: E N
authors: EN
authors: Howe
authors: N S
authors: NS
authors: Spoelstra
authors: S D
authors: SD
authors: Axlund
authors: P
authors: P
authors: Hendricks
authors: B M
authors: BM
authors: Jacobsen
authors: C A
authors: CA
authors: Sartorius
authors: J K
authors: JK
authors: Richer
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D011372:Progestins; D011374:Progesterone