Deregulated ephrin-B2 expression in the mammary gland interferes with the development of both the glandular epithelium and vasculature and promotes metastasis formation.
Eph receptor tyrosine kinases and their membrane-bound ephrin ligands play key roles during morphogenesis and adult tissue homeostasis. Receptor-ligand interactions result in forward and reverse signalling from the receptor and ligand respectively. To delineate the role(s) of forward and reverse signalling in mammary gland biology we have established transgenic mice exhibiting mammary epithelial-specific overexpression of either the native ephrin-B2 or a dominant negative ephrin-B2 mutant incapable of reverse signalling. During pregnancy and lactation overexpression of the native ephrin-B2 resulted in precocious differentiation, whereas overexpression of mutated ephrin-B2 caused delayed epithelial differentiation and in disturbed tissue architecture. Both transgenes affected also mammary vascularisation. Whereas ephrin-B2 induced superfluous but organised capillaries, mutant ephrin-B2 overexpression resulted in an irregular vasculature with blind-ending capillaries. Mammary tumours were not observed in either transgenic line, however, the crossing with NeuT transgenic animals revealed that mutated ephrin-B2 expression significantly accelerated tumour growth and imposed a metastatic phenotype.
Haldimann
Mirjam
M
Department of Clinical Research, University of Bern, Tiefenaustrasse 120, Bern, Switzerland.
Custer
Domenica
D
Munarini
Nadia
N
Stirnimann
Christoph
C
Zürcher
Gisela
G
Rohrbach
Valeria
V
Djonov
Valentin
V
Ziemiecki
Andrew
A
Andres
Anne-Catherine
AC
D000818:Animals; D036388:Ephrin-B2 / Q000096:biosynthesis / Q000235:genetics*; D004848:Epithelium / Q000254:growth & development / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000098:blood supply* / Q000254:growth & development* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D036388:Ephrin-B2; D012333:RNA, Messenger