title: Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a.
abstract: Progesterone (P4) has emerged as an important hormone-regulating mammary stem cell (MaSC) populations. In breast cancer, P4 and synthetic analogs increase the number of stem-like cells within luminal estrogen receptor (ER)- and progesterone receptor (PR)-positive breast cancers. These cells gain expression of de-differentiated cell markers CD44 and cytokeratin 5 (CK5), lose luminal markers ER and PR, and are more therapy resistant. We previously described that P4 downregulation of microRNA (miR)-29a contributes to the expansion of CD44(high) and CK5(+) cells. Here we investigated P4 downregulation of miR-141, a member of the miR-200 family of tumor suppressors, in facilitating an increase in stem-like breast cancer cells. miR-141 was the sole member of the miR-200 family P4-downregulated at the mature miRNA level in luminal breast cancer cell lines. Stable inhibition of miR-141 alone increased the CD44(high) population, and potentiated P4-mediated increases in both CD44(high) and CK5(+) cells. Loss of miR-141 enhanced both mammosphere formation and tumor initiation. miR-141 directly targeted both PR and signal transducer and activator of transcription 5A (Stat5a), transcription factors important for MaSC expansion. miR-141 depletion increased PR protein levels, even in cell lines where PR expression is estrogen dependent. Stat5a suppression via small interfering RNA or a small-molecule inhibitor reduced the P4-dependent increase in CK5(+) and CD44(high) cells. These data support a mechanism by which P4-triggered loss of miR-141 facilitates breast cancer cell de-differentiation through deregulation of PR and Stat5a, two transcription factors important for controlling mammary cell fate.
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Finlay-Schultz
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Cittelly
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hendricks
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Patel
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kabos
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Jacobsen
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Richer
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Sartorius
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D053555:Keratin-5 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D011980:Receptors, Progesterone; D050799:STAT5 Transcription Factor / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D053555:Keratin-5; C533895:MIRN141 microRNA, human; D035683:MicroRNAs; D011372:Progestins; D011980:Receptors, Progesterone; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D011374:Progesterone