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Cancer Res. 2013 Sep 15;73(18):5719-29. doi: 10.1158/0008-5472.CAN-13-0021. Epub 2013 Jul 18.

Epimorphin is a novel regulator of the progesterone receptor isoform-a.

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1
Authors' Affiliations: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California; Mayo Clinic Cancer Center, Jacksonville, Florida; College of Staten Island, City University of New York, Staten Island, New York; and Department of Bioscience, Kwansei Gakuin University, Sanda, Japan.

Abstract

Epimorphin/syntaxin-2 is a membrane-tethered protein localized extracellularly (Epim) and intracellularly (Stx-2). The extracellular form Epim stimulates morphogenic processes in a range of tissues, including in murine mammary glands where its overexpression in luminal epithelial cells is sufficient to drive hyperplasia and neoplasia. We analyzed WAP-Epim transgenic mice to gain insight into how Epim promotes malignancy. Ectopic overexpression of Epim during postnatal mammary gland development led to early side-branching onset, precocious bud formation, and increased proliferation of mammary epithelial cells. Conversely, peptide-based inhibition of Epim function reduced side branching. Because increased side branching and hyperplasia occurs similarly in mice upon overexpression of the progesterone receptor isoform-a (Pgr-a), we investigated whether Epim exhibits these phenotypes through Pgr modulation. Epim overexpression indeed led to a steep upregulation of both total Pgr mRNA and Pgr-a protein levels. Notably, the Pgr antagonist RU486 abrogated Epim-induced ductal side branching, mammary epithelial cell proliferation, and bud formation. Evaluation of Epim signaling in a three-dimensional ex vivo culture system showed that its action was dependent on binding to its extracellular receptor, integrin-αV, and on matrix metalloproteinase 3 activity downstream of Pgr-a. These findings elucidate a hitherto unknown transcriptional regulator of Pgr-a, and shed light on how overexpression of Epim leads to malignancy.

PMID:
23867473
PMCID:
PMC3783262
DOI:
10.1158/0008-5472.CAN-13-0021
[Indexed for MEDLINE]
Free PMC Article

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