Haldimann Mirjam, Custer Domenica, Munarini Nadia, Stirnimann Christoph, Zürcher Gisela, Rohrbach Valeria, Djonov Valentin, Ziemiecki Andrew, Andres Anne-Catherine
Department of Clinical Research, University of Bern, Tiefenaustrasse 120, Bern, Switzerland.
Int J Oncol. 2009 Sep;35(3):525-36. doi: 10.3892/ijo_00000364.
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.
Eph受体酪氨酸激酶及其膜结合的ephrin配体在形态发生和成年组织稳态过程中发挥关键作用。受体-配体相互作用分别导致来自受体和配体的正向和反向信号传导。为了阐明正向和反向信号传导在乳腺生物学中的作用，我们建立了转基因小鼠，其表现出乳腺上皮特异性过表达天然ephrin-B2或不能进行反向信号传导的显性负性ephrin-B2突变体。在怀孕和哺乳期，天然ephrin-B2的过表达导致早熟分化，而突变的ephrin-B2的过表达导致上皮分化延迟和组织结构紊乱。两种转基因也影响乳腺血管生成。虽然ephrin-B2诱导了多余但有组织的毛细血管，但突变的ephrin-B2过表达导致血管不规则，毛细血管盲端。在任何一个转基因品系中均未观察到乳腺肿瘤，然而，与NeuT转基因动物杂交显示，突变的ephrin-B2表达显著加速肿瘤生长并呈现转移表型。
