THE EXPRESSION OF AN ETS1 TRANSCRIPTION FACTOR LACKING ITS ACTIVATIONDOMAIN DECREASES UPA PROTEOLYTIC ACTIVITY AND CELL MOTILITY, AND IMPAIRS NORMAL TUBULOGENESIS AND CANCEROUS SCATTERING IN MAMMARY EPITHELIAL-CELLS

Cell migration and invasion play a crucial role during normal and path ological development. The expression of several members of the Ets fam ily of transcription factors has been shown to correlate with the occu rrence of these processes. In the present study, we investigated the e ffect of the expression of Ets1-DB, the DNA-binding domain of c-Ets1, on the functional properties of NMuMG and MMT epithelial cell lines, f rom normal and cancerous mouse mammary tissues, respectively. We found that stable expression of this Ets1-DB mutant inhibited, in both cell types, the gene expression and activity of urokinase type-plasminogen activator (uPA), a potential target of c-Ets1.uPA is a key serine pro teinase in the proteolytic cascade leading to the degradation of the e xtracellular matrix, In two-dimensional cultures, expression of the Et s1-DB mutant resulted in a decrease in cell migration and invasion in both cell lines. In three-dimensional collagen gels, NMuMG cells under went tubular morphogenesis, while MMT cells developed as scattered str uctures. The Ets1-DB mutant impaired the capacity of NMuMG cells to fo rm tubules and reduced the ability of MMT cells to invade these gels. Similar inhibition of cell migration, invasion and morphogenesis were observed in non-infected NMuMG and MMT cell lines treated with aprotin in, a serine proteinase inhibitor, suggesting that the inhibition of t he plasmin cascade mediates in part the biological effects induced by the Ets1-DB mutant. These results demonstrate that Ets family members are involved in the control of uPA activity, cell motility and invasio n during normal tubular morphogenesis and cancerous scattering in mamm ary epithelial cells.