Activation of beta -catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias.
Mammary anlagen are formed in the embryo as a derivative of the epidermis, a process that is controlled by Lef-1 and therefore possibly by beta-catenin. To investigate the role of beta-catenin signaling in mammary alveolar epithelium, we have stabilized endogenous beta-catenin in differentiating alveolar epithelium through the deletion of exon 3 (amino acids 5-80) of the beta-catenin gene. This task was accomplished in mice carrying a floxed beta-catenin gene and a Cre transgene under control of the mammary-specific whey acidic protein (WAP) gene promoter or the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Stabilized beta-catenin was obtained during the first pregnancy, and its presence resulted in the dedifferentiation of alveolar epithelium followed by a transdifferentiation into epidermal and pilar structures. Extensive squamous metaplasia, but no adenocarcinomas, developed upon beta-catenin activation during pregnancy and persisted throughout involution. These data demonstrate that the activation of beta-catenin signaling induces a program that results in loss of mammary epithelial cell differentiation and induction of epidermal structures.
Miyoshi
Keiko
K
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Shillingford
Jonathan M
JM
Le Provost
Fabienne
F
Gounari
Fotini
F
Bronson
Roderick
R
von Boehmer
Harald
H
Taketo
Makoto M
MM
Cardiff
Robert D
RD
Hennighausen
Lothar
L
Khazaie
Khashayarsha
K
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002454:Cell Differentiation; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology; D005091:Exons; D017353:Gene Deletion; D007150:Immunohistochemistry; D008679:Metaplasia / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008894:Milk Proteins / Q000235:genetics; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008894:Milk Proteins; D015534:Trans-Activators; D051176:beta Catenin; C024471:whey acidic proteins