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Epimorphin Overexpression in the Mouse Mammary Gland Promotes Alveolar Hyperplasia and Mammary Adenocarcinoma

¹ Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California; ² Department of Morphoregulation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan; and ³ Department of Anatomy, University of California, San Francisco, California

Requests for reprints: Mina J. Bissell, Lawrence Berkeley National Laboratory, Mailstop 977R-225A, 1 Cyclotron Road, Berkeley, CA 94720. Phone: 510-486-4365; Fax: 510-486-5586; E-mail: MJBissell{at}lbl.gov.

Epimorphin/syntaxin-2 (EPM) is a plasma membrane–anchored protein that has at least two distinct functions depending on its membrane topology: vesicle fusion when localized to the cytoplasmic surface and morphogenic signaling when localized to the extracellular surface. Transgenic mice that express full-length extracellular EPM fused to the NH₂-terminal signal sequence of interleukin-2, under the control of the whey acidic protein (WAP) gene promoter, exhibit aberrant mammary gland morphogenesis associated with increased expression of CCAAT enhancer binding protein ß (C/EBPß). Here we report that aged nulliparous and uniparous female WAP-EPM transgenic mice develop alveolar hyperplasias and well-differentiated adenocarcinomas that express high levels of C/EBPß, keratin-14, matrix metalloproteinase-3, and ß-catenin. This study reveals another pathway in which overexpression and alteration of a normal morphogenic process promote the development of cancer in the mammary gland.

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