title: Epimorphin is a novel regulator of the progesterone receptor isoform-a.
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.
authors.affiliation: 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.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Bascom
authors.forename: Derek C
authors.initials: DC
authors.lastname: Radisky
authors.forename: Eileen
authors.initials: E
authors.lastname: Koh
authors.forename: Jimmie E
authors.initials: JE
authors.lastname: Fata
authors.forename: Alvin
authors.initials: A
authors.lastname: Lo
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Mori
authors.forename: Neda
authors.initials: N
authors.lastname: Roosta
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hirai
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C504582:Epim protein, mouse; D006727:Hormone Antagonists; D008562:Membrane Glycoproteins; D008894:Milk Proteins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; C024471:whey acidic proteins; D015735:Mifepristone