Nikolova Z, Djonov V, Zuercher G, Andres A C, Ziemiecki A
Department of Clinical Research, University of Berne, Tiefenaustrasse 120, CH-3004 Berne, Switzerland.
J Cell Sci. 1998 Sep;111 ( Pt 18):2741-51. doi: 10.1242/jcs.111.18.2741.
Morphogenesis of the mammary gland occurs mainly during adult life and is dependent on a complex interplay of hormonal, cell-cell and cell-matrix interactions. The molecular mechanisms involved in pattern formation of the mammary epithelium in adult life are poorly understood. Recently, several members of the Eph family of receptor tyrosine kinases and their ligands have been shown to participate in pattern formation during embryogenesis and conceivably may fulfill similar functions during adult morphogenesis. We have investigated the expression of a member of this family, EphB4, and its cognate ligand, ephrin-B2, during normal and malignant mouse mammary morphogenesis. A spatially, temporarily and hormonally coordinated expression of both the receptor and ligand was observed. The receptor was predominantly localized in the myoepithelial cells surrounding the ducts and alveoli whereas ligand expression was limited to the luminal epithelial cells. Expression of both was induced at the onset of gland morphogenesis at puberty and was differentially regulated during the estrus cycle. Ovariectomy of pre-pubertal or adult females abolished the expression of both receptor and ligand and administration of estrogen alone was sufficient to restore their normal expression. Disruption of the balanced expression was observed during experimental mouse mammary carcinogenesis. Ligand expression was lost at the onset of tumorigenesis and receptor expression shifted from myoepithelial to epithelial cells with progressive malignancy. These results implicate both the EphB4 receptor and its ligand ephrin-B2 in the hormone dependent morphogenesis of the mammary gland. Furthermore, their deregulated expression may contribute to mammary carcinogenesis.
乳腺的形态发生主要发生在成年期，并且依赖于激素、细胞 - 细胞以及细胞 - 基质相互作用之间复杂的相互影响。目前对于成年期乳腺上皮细胞模式形成所涉及的分子机制了解甚少。最近，受体酪氨酸激酶Eph家族的几个成员及其配体已被证明参与胚胎发育过程中的模式形成，并且可以想象在成年形态发生过程中可能发挥类似的功能。我们研究了该家族成员之一EphB4及其同源配体ephrin - B2在正常和恶性小鼠乳腺形态发生过程中的表达情况。观察到受体和配体在空间、时间和激素方面的协调表达。受体主要定位于导管和腺泡周围的肌上皮细胞，而配体表达仅限于管腔上皮细胞。两者的表达在青春期腺体形态发生开始时被诱导，并且在发情周期中受到差异调节。对青春期前或成年雌性小鼠进行卵巢切除会消除受体和配体的表达，单独给予雌激素足以恢复它们的正常表达。在实验性小鼠乳腺癌发生过程中观察到平衡表达的破坏。在肿瘤发生开始时配体表达丧失，并且随着恶性程度的进展，受体表达从肌上皮细胞转移到上皮细胞。这些结果表明EphB4受体及其配体ephrin - B2都参与乳腺的激素依赖性形态发生。此外，它们的表达失调可能导致乳腺癌的发生。
