title: Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk.
abstract: Ovarian hormones increase breast cancer risk by poorly understood mechanisms. We assess the role of progesterone on global stem cell function by serially transplanting mouse mammary epithelia. Progesterone receptor (PR) deletion severely reduces the regeneration capacity of the mammary epithelium. The PR target, receptor activator of Nf-κB ligand (RANKL), is not required for this function, and the deletion of Wnt4 reduces the mammary regeneration capacity even more than PR ablation. A fluorescent reporter reveals so far undetected perinatal Wnt4 expression that is independent of hormone signaling. Pubertal and adult Wnt4 expression is specific to PR+ luminal cells and requires intact PR signaling. Conditional deletion of Wnt4 reveals that this early, previously unappreciated, Wnt4 expression is functionally important. We provide genetic evidence that canonical Wnt signaling in the myoepithelium required PR and Wnt4, whereas the canonical Wnt signaling activities observed in the embryonic mammary bud and in the stroma around terminal end buds are independent of Wnt4. Thus, progesterone and Wnt4 control stem cell function through a luminal-myoepithelial crosstalk with Wnt4 acting independent of PR perinatally.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Renuga Devi
authors.initials: RD
authors.lastname: Rajaram
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Duje
authors.initials: D
authors.lastname: Buric
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Marian
authors.initials: M
authors.lastname: Caikovski
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
authors.forename: Ayyakkannu
authors.initials: A
authors.lastname: Ayyanan
authors.affiliation: Swiss Institute of Bioinformatics Bioinformatics and Biostatistics Core Facility Ecole polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rougemont
authors.affiliation: Faculty of Biochemisty and Molecular Medicine (FBMM), Biocenter Oulu and Infotech Oulu Oulu Center for Cell Matrix Research University of Oulu, Oulu, Finland.
authors.forename: Jingdong
authors.initials: J
authors.lastname: Shan
authors.affiliation: Faculty of Biochemisty and Molecular Medicine (FBMM), Biocenter Oulu and Infotech Oulu Oulu Center for Cell Matrix Research University of Oulu, Oulu, Finland.
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
authors.affiliation: Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey.
authors.forename: Ozden
authors.initials: O
authors.lastname: Yalcin-Ozuysal
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL) ISREC - Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland cathrin.brisken@epfl.ch.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Brisken
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004848:Epithelium / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D006652:Histological Techniques; D007091:Image Processing, Computer-Assisted; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000196:embryology* / Q000502:physiology; D051379:Mice; D008856:Microscopy, Fluorescence; D011374:Progesterone / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology; D011980:Receptors, Progesterone / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D060528:Wnt4 Protein / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D011980:Receptors, Progesterone; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D011374:Progesterone
keywords: canonical Wnt signaling; hormones; mammary stem cells; myoepithelium; paracrine