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

Jamie L. Bascom, Derek C. Radisky, Eileen Koh, Jimmie E. Fata, Alvin Lo, Hidetoshi Mori, Neda Roosta, Yohei Hirai, Mina J. Bissell

Research output: Contribution to journalArticle

5 Scopus citations

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-aV, 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.

Original languageEnglish (US)
Pages (from-to)5917-5929
Number of pages13
JournalCancer Research
Volume73
Issue number18
DOIs
StatePublished - Sep 15 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bascom, J. L., Radisky, D. C., Koh, E., Fata, J. E., Lo, A., Mori, H., Roosta, N., Hirai, Y., & Bissell, M. J. (2013). Epimorphin is a novel regulator of the progesterone receptor isoform-A. Cancer Research, 73(18), 5917-5929. https://doi.org/10.1158/0008-5472.CAN-13-0021