Activation of β-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias

doi:10.1073/pnas.012414099

Activation of β-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias

^*Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; ^§Laboratoire de Génétique biochimique et de Cytogénétique, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cedex, France; ^¶Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 20215; ^‖Department of Pharmacology, Kyoto University Graduate School of Medicine, Sakyo, Kyoto 606-8501, Japan; and ^**Center for Comparative Medicine, University of California, Davis, CA 95616

Edited by Philip Leder, Harvard Medical School, Boston, MA, and approved October 26, 2001 (received for review August 6, 2001)

Abstract

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 β-catenin. To investigate the role of β-catenin signaling in mammary alveolar epithelium, we have stabilized endogenous β-catenin in differentiating alveolar epithelium through the deletion of exon 3 (amino acids 5–80) of the β-catenin gene. This task was accomplished in mice carrying a floxed β-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 β-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 β-catenin activation during pregnancy and persisted throughout involution. These data demonstrate that the activation of β-catenin signaling induces a program that results in loss of mammary epithelial cell differentiation and induction of epidermal structures.

mammary gland‖cell identity‖Wnt-signaling‖Cre‖dedifferentiation

Footnotes

↵ † K.M. and J.M.S. contributed equally to this work.
↵ ‡ Present address: Department of Biochemistry, School of Dentistry, University of Tokushima, Tokushima, 770-8504, Japan.
↵ †† To whom reprint requests should be addressed. E-mail: hennighausen{at}nih.gov or khashayarsha_khazaie{at}dfci.harvard.edu.
This paper was submitted directly (Track II) to the PNAS office.
** L.H. and K.K. contributed equally to this work.
Abbreviations:

LEF,

lymphoid enhancer transcription factor;

MMTV-LTR,

mouse mammary tumor virus-long terminal repeat;

WAP,

whey acidic protein;

NKCC1,

Na-K-Cl cotransporter 1;

Npt2b,

Na-Pi cotransporter type II b