THE EFFECTS OF THE NEUN AND NEUT GENES ON DIFFERENTIATION AND TRANSFORMATION OF MAMMARY EPITHELIAL-CELLS

Overexpression of the proto-oncogene product, p185(neuN), in a non-tum origenic mammary epithelial line (31E) facilitates aspects of lactogen ic differentiation. Formation of branching cords and induction of beta -casein synthesis by 31E cells normally require co-culture of these ce lls with fibroblasts, or the presence of collagen or fibronectin. In c ontrast, 31E cells expressing p185(neuN) spontaneously form branching cords when grown on tissue culture plastic and can synthesize beta-cas ein in the absence of exogenous substrates or feeder layers. Under the se conditions, the cells deposit laminin and fibronectin, indicating a possible role for p185(neuN) in the deposition of extracellular matri x proteins. Overexpression of the corresponding oncogene product, p185 (neuT), has markedly different effects. Expression of p185(neuT) does not facilitate the formation of branching cords or the synthesis of be ta-casein when grown on tissue culture plastic, although these cells d o deposit laminin and fibronectin. Confocal microscopy indicates a sig nificant difference in the distribution of laminin and fibronectin in 31E cells expressing p185(neuT) compared to those expressing p185(neuN ). The effects of p185(neuN) and p185(neuT) expression on cell transfo rmation depend on cell type. Expression of both p185(neuN) and p185(ne uT) increases anchorage-independent growth of 31E cells, but only p185 (neuT) induces anchorage-independent growth of NIH 3T3 fibroblasts. Th is lineage specificity in the action of p185(neuN) may be related to o bservations that overexpression of p185(c-erbB-2) (the human homologue of p185(neuN)) is only associated with the development of human epith elial cancers. The effects of p185(neuN) on laminin deposition by 31E cells may be relevant to the transforming ability of p185(neuN), since laminin can induce anchorage-independent growth of mouse mammary cell s. These results suggest that p185(neuN) and p185(neuT) could exert th eir effects on differentiation and transformation of mammary epithelia l cells in part by promoting the deposition of extracellular matrix pr oteins.