Abstract
Matrix metalloproteinase-9 (MMP-9) plays important roles in tumor invasion and angiogenesis. Secretion of MMP-9 has been reported in various cancer types including lung cancer, colon cancer, and breast cancer. In our investigation of MMP-9 regulation by growth factors, MMP-9 was activated by heregulin-β as shown by zymography in both SKBr3 and MCF-7 breast cancer cell lines. Increase in MMP-9 activity was due to increased MMP-9 protein and mRNA levels, which mainly results from transcriptional upregulation of MMP-9 by heregulin-β1. Heregulin-β1 activates multiple signaling pathways in breast cancer cells, including Erk, p38 kinase, PKC, and PI3-K pathways. We examined the pathways involved in heregulin-β1-mediated MMP-9 activation using chemical inhibitors that specifically inhibit each of these heregulin-β1-activated pathways. The PKC inhibitor RO318220 and p38 kinase inhibitor SB203580 completely blocked heregulin-β1-mediated activation of MMP-9. MEK-1 inhibitor PD098059 partially blocked MMP-9 activation, whereas PI3-K inhibitor wortmannin had no effect on heregulin-β1-mediated MMP-9 activation. Therefore, at least three signaling pathways are involved in the activation of MMP-9 by heregulin-β1. Since MMP-9 is tightly associated with invasion/metastasis and angiogenesis, our studies suggest that blocking heregulin-β1-mediated activation of MMP-9 by inhibiting the related signaling pathways may provide new strategies for inhibition of cancer metastasis and angiogenesis.
Original language | English (US) |
---|---|
Pages (from-to) | 8066-8074 |
Number of pages | 9 |
Journal | Oncogene |
Volume | 20 |
Issue number | 56 |
DOIs | |
State | Published - Dec 6 2001 |
Keywords
- Breastcancer
- Heregulin-β1
- Invasion
- MMP-9
- Signaling
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research