MODULATION OF HUMAN STROMELYSIN-3 PROMOTER ACTIVITY AND GENE-EXPRESSION BY HUMAN BREAST-CANCER CELLS

The matrix-degrading enzyme family of matrix-metalloproteinases (MMPs) has been implicated in the process of tumour metastasis, Cellular pro tein and RNA localisation techniques have been used to show that, whil st several MMP genes are expressed in both cancer and stromal cells, s tromelysin 3 is expressed only in stromal fibroblasts adjacent to canc er cells, Immunohistochemical and in situ hybridisation evidence sugge sts that neoplastic cells can stimulate stromal cell MMP production ei ther in a paracrine fashion or by a cell-cell contact mechanism, Using 2 different lengths of the human stromelysin 3 (ST3) gene 5' flanking sequence cloned upstream of luciferase and CAT reporter genes, we now show that human breast cancer cells can directly activate the ST3 pro moter, The putative response element in the ST3 promoter, which lies b etween 0.46 and 3.4 kb upstream of the transcription start site, is ab le to effect a 2- to 3-fold increase in downstream gene expression, We further show that this transcriptional up-regulation definitely occur s via a paracrine, and possibly via a cell-cell contact, mechanism. Co nfirmation that this ST3 promoter activation results in ST3 gene induc tion of a similar magnitude was shown using Northern blotting of stimu lated fibroblasts. Our data provide further evidence that cancer cells can induce fibroblast MMP expression and help to explain the in vivo expression pattern of ST3 in breast cancer. (C) 1997 Wiley-Liss, Inc.