Collagenases in Breast Cancer Cell-Induced Metastatic Tumor Growth and Progression

摘要

Since collagenases (-1 and -3) degrade the extracellular bone matrix (ECM) components, collagenase-driven ECM proteolysis may facilitate cancer growth and progression. To test this hypothesis, we made a transgene construct containing collagenase-1 cDNA under the control of the bone specific osteocalcin promoter. The application of a transgenic mouse model will contribute greatly to the understanding of the pathogenesis of bone metastasis. Transforming growth factor (TGF)-Beta1 is a crucial molecule in metastatic breast cancer. It can potentially disrupt the normal balance between osteoclast- and osteoblast- derived matrix metalloproteinase (MMP) activity within bone by inducing. the expression of MMPs and their inhibitors from bone-metastasizing cancer cells. TGF-Beta1 stimulates collagenase-3 expression in human breast cancer cells (metastatic in nature) . An intensive drug discovery program led to many clinical trials of MMP inhibitors for cancer therapy. However, these trials have largely been disappointing. A greater Understanding of the regulatory mechanisms that control MMP transcription, activation and inhibition will proyide several new avenues for therapeutic intervention. Here, we dissected the signaling and molecular mechanisms responsible for TGF-Beta1 stimulated collagenase-3 expression in human breast cancer cells.