1. Epimorphin Is a Novel Regulator of the Progesterone Receptor Isoform-A
- Author
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Jamie L. Bascom, Derek C. Radisky, Yohei Hirai, Jimmie E. Fata, Mina J. Bissell, Eileen Koh, Alvin Lo, Neda Roosta, and Hidetoshi Mori
- Subjects
Male ,endocrine system ,Cancer Research ,Blotting, Western ,Apoptosis ,Mice, Transgenic ,Progesterone Receptor Isoform A ,Biology ,Real-Time Polymerase Chain Reaction ,Article ,Mice ,Hormone Antagonists ,Mammary Glands, Animal ,Downregulation and upregulation ,Pregnancy ,Progesterone receptor ,Extracellular ,medicine ,Animals ,Humans ,RNA, Messenger ,skin and connective tissue diseases ,Receptor ,Cell Proliferation ,Regulation of gene expression ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Milk Proteins ,Molecular biology ,Epithelium ,Cell biology ,Mifepristone ,Phenotype ,medicine.anatomical_structure ,Gene Expression Regulation ,Oncology ,Female ,Receptors, Progesterone ,hormones, hormone substitutes, and hormone antagonists - 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. Cancer Res; 73(18); 5719–29. ©2013 AACR.
- Published
- 2013
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