EXTRACELLULAR-MATRIX REGULATES WHEY ACIDIC PROTEIN GENE-EXPRESSION BYSUPPRESSION OF TGF-ALPHA IN MOUSE MAMMARY EPITHELIAL-CELLS - STUDIES IN CULTURE AND IN TRANSGENIC MICE

Whey acidic protein (WAP) is an abundant rodent milk protein. Its expr ession in mouse mammary epithelial cell cultures was previously found to require the formation of an extracellular matrix (ECM)-induced thre e-dimensional alveolar structure. In the absence of such structures, c ells were shown to secrete diffusible factors leading to suppression o f WAP expression. We demonstrate here that (a) TGF-alpha production an d secretion by mammary cells is downregulated by the basement membrane -dependent alveolar structure, and (b) compared with beta-casein, WAP expression is preferentially inhibited both in culture and in transgen ic mice when TGF-alpha is added or overexpressed. Thus, (c) the enhanc ed TGF-alpha production when cells are not in three-dimensional struct ures largely accounts for the WAP-inhibitory activity found in the con ditioned medium. Since this activity can be abolished by incubating th e conditioned medium with a function blocking antibody to TGF-alpha. T he data suggest that ECM upregulates WAP by downregulating TGF-alpha p roduction. We also propose that changes in TGE-alpha activity during m ouse gestation and lactation could contribute to the pattern of tempor al expression of WAP in the gland. These results provide a clear examp le of cooperation among lactogenic hormones, ECM, and locally acting g rowth factors in regulation of tissue-specific gene expression.