Transforming growth factor beta 1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells

Bone metastases are a common complication in prostate and breast cancer pat ients. It leads to extensive morbidity and eventually mortality. Matrix met alloproteinases (MMPs) are known to be involved in the metastatic process. MMP activity can be down-regulated by transforming growth factor beta 1 (TG F-beta 1), a growth-modulating factor, found in high concentrations in the bone. TGF-beta 1 acts through the TGF-beta 1 inhibitory element (TIE) eleme nt, a cis-acting element found in the promoter region of most MMP genes, wi th the exception of MMP-2. We used three human cell lines relevant for bone metastases, namely prostate adenocarcinoma PC-3, breast adenocarcinoma MDA -MB-231, and adenocarcinoma cells of unknown origin, Hs696, and one human o steosarcoma cell line, SAOS-2, and showed that in these cell lines TGF-beta 1 partially lost its repressing action on MMP expression. TGF-beta 1 was a ble to induce MMP-9 activity and protein expression in all three bone-metas tatic tumour cell types, whereas MMP-9 protein levels were repressed in SAO S-2 cells. In PC-3 cells, TGF-beta 1 repressed MMP-1 expression, whereas in MDA-MB-231 and SAOS-2 cells, an increase in the expression of MMP-1 protei n was detected. Additionally, an increase in MMP-3 expression was observed in Hs696 cells. Expression and activity of the tissue inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, were found increased in both PC-3 an d MDA-MB-231 cells. With respect to cell proliferation, TGF-beta 1 was able to induce a dose-dependent growth inhibition of up to 50% in primary human mammary epithelial cells. However, in none of the tumour cell lines was TG F-beta 1 able to suppress growth substantially. Data presented in this pape r support the hypothesis that TGF-beta 1 can potentially disrupt the balanc e existing between osteoclast- and osteoblast-derived MMP activity by induc ing altered expression of matrix metalloproteinases and their tissue inhibi tors derived from bone-metastasizing cancer cells. This could eventually le ad to skeletal destruction in patients with advanced metastatic disease.