EXPRESSION OF C-ETS-1 MESSENGER-RNA IS ASSOCIATED WITH AN INVASIVE, EMT-DERIVED PHENOTYPE IN BREAST-CARCINOMA CELL-LINES

We have previously observed in vitro that some stromal proteinases (MM P-2, MT1-MMP) were expressed or activated by invasive carcinoma cell l ines exhibiting mesenchymal features, presumably acquired through an e pithelial to mesenchymal transition (EMT). To examine the potential co ntribution of c-ets-l to this phenotype, we have compared here the exp ression of c-ets-l with invasiveness in vitro and expression of viment in, E-cadherin, uPA, MMP-1 and MMP-3 in a panel of human breast cancer cell lines. Our results clearly demonstrate an association between c- ets-l expression and the invasive, EMT-derived phenotype, which is typ ified by the expression of vimentin and the lack of E-cadherin. While absent from the two non-invasive, vimentin-negative cell lines, c-ets- l was abundantly expressed in all the four vimentin-positive lines. Ho wever, we could not find a clear quantitative or qualitative relations hip between the expression of c-ets-1 and the three proteinases known to be regulated by c-ets-l, except that when they were expressed, it w as only in the invasive c-ets-1-positive lines. UPA mRNAs were found i n three of the four vimentin-positive lines, MMP-1 in two of the four, and MMP-3 could not be detected in any of the cell lines. Intriguingl y, MDA-MB-435 cells, which exhibit the highest metastatic potential of these cell lines in nude mice, expressed vimentin and c-ets-l, but la cked expression of these three proteinases, at least under the culture conditions employed. Taken together, our results show that c-ets-l ex pression is associated with an invasive, EMT-derived phenotype in brea st cancer cells, although it is apparently not sufficient to ensure th e expression of uPA, MMP-1 or MMP-3, in the vimentin-positive cells. S uch proteases regulation is undoubtedly qualified by the cellular cont ext. This study therefore advances our understanding of the molecular regulation of invasiveness in EMT-associated carcinoma progression, an d suggests that c-ets-l may contribute to the invasive phenotype in ca rcinoma cells.