ROLE OF MORPHOGENETIC FACTORS IN METASTASIS OF MAMMARY-CARCINOMA CELLS

We have analysed the role of the morphogenetic factors hepatocyte grow th factor/scatter factor (HGF), neuregulin and E-cadherin in the proce ss of metastasis and morphogenesis of mammary carcinoma cells. The cDN As for HGF, neuregulin and E-cadherin were stably expressed in anaplas tic human MDA MB 435 carcinoma cells. The altered cells were then inje cted into the mammary fat pads of nude mice, where they form tumors wh ich can spontaneously metastasize to the lungs. We found that expressi on of HGF or neuregulin promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form morphoge netic structures in matrigel cultures in response to HGF. These data d emonstrate that HGF and neuregulin, which control branching or lobulo- alveolar morphogenesis of normal breast epithelium, do have metastasis -promoting effects on breast carcinoma cells. Moreover, our results su ggest that the differential activities of the two factors can be expla ined by the degree of epithelial differentiation: induction of morphog enesis requires an intact epithelial adhesion and differentiation syst em, whereas induction of metastasis is observed when the cells have lo st their epithelial characteristics.