CELL-TYPE-SPECIFIC AND ESTROGEN-DEPENDENT EXPRESSION OF THE RECEPTOR TYROSINE KINASE EPHB4 AND ITS LIGAND EPHRIN-B2 DURING MAMMARY-GLAND MORPHOGENESIS

Morphogenesis of the mammary gland occurs mainly during adult life and is dependent on a complex interplay of hormonal, cell-cell and cell-m atrix interactions. The molecular mechanisms involved in pattern forma tion of the mammary epithelium in adult life are poorly understood, Re cently, 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 du ring adult morphogenesis, We have investigated the expression of a mem ber of this family, EphB4, and its cognate ligand, ephrin-B2, during n ormal and malignant mouse mammary morphogenesis, A spatially, temporar ily and hormonally coordinated expression of both the receptor and lig and was observed. The receptor was predominantly localized in the myoe pithelial cells surrounding the ducts and alveoli whereas ligand expre ssion was limited to the luminal epithelial cells, Expression of both was induced at the onset of gland morphogenesis at puberty and was dif ferentially regulated during the estrus cycle. Ovariectomy of prepuber tal or adult females abolished the expression of both receptor and lig and and administration of estrogen alone was sufficient to restore the ir normal expression, Disruption of the balanced expression was observ ed during experimental mouse mammary carcinogenesis, Ligand expression was lost at the onset of tumorigenesis and receptor expression shifte d 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, Furthe rmore, their deregulated expression may contribute to mammary carcinog enesis.