Downregulation of fibronectin transcription in highly metastatic adenocarcinoma cells

Silencing of fibronectin (FN) expression seems to be one of the key mechani sms underlying metastatic behaviour. An inverse correlation exists between FN expression levels and the metastatic potential of two related murine mam mary adenocarcinomas, M3 and MM3. Primary cultures of M3 tumour, which is m oderately metastatic to lung (40% incidence), show a conspicuous FN extrace llular matrix (ECM) and high levels of FN mRNA, while primary cultures of t he highly metastatic MM3 tumour (95% lung incidence) are negative for FN in immunofluorescence and show at least 40-fold lower levels of FN mRNA, only detectable by RT-PCR, with a different pattern of alternatively spliced ED I isoforms compared to M3 cells. We show that the FN promoter sequence is n ot altered in MM3 cells, Transfection experiments with CAT constructs indic ate that silencing occurs at the transcriptional level, involving the 220-b p proximal promoter region. (C) 1998 Federation of European Biochemical Soc ieties.