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Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-β1 in human breast cancer cells

Oncogene volume 20, pages 8066–8074 (2001)Cite this article

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-β1 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.

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Abbreviations

MMP-9:

matrix metalloproteinase-9

Erk:

extracellular response kinase

PKC:

protein kinase C

PI3-K:

phosphatidylinositol 3-kinase

PMA:

phorbol 12-myristate 13-acetate

JNK:

Jun amino-terminus kinase

TGF:

transforming growth factor.

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Acknowledgements

We thank Dr Douglas Boyd for valuable reagents. This research was supported by grants P30-CA16672 and 2RO1-CA60448 (to D Yu) from the National Institutes of Health; DAMD17-98-2-8338 (to D Yu) and DAMD17-99-1-9271 to (D Yu) from the United States Army Research and Material Command; and The University of Texas M.D. Anderson Breast Cancer Basic Research Program Fund (to D Yu). J Yao is an awardee of the Rosalie B Hite predoctoral fellowship.

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  1. Jun Yao and Shunbin Xiong: J Yao and S Xiong contributed equally to this paper

Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Jun Yao, Shunbin Xiong, Kristine Klos, Nina Nguyen, Rebecca Grijalva, Ping Li & Dihua Yu

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  1. Jun Yao
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Correspondence to Dihua Yu.

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Yao, J., Xiong, S., Klos, K. et al. Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-β1 in human breast cancer cells. Oncogene 20, 8066–8074 (2001). https://doi.org/10.1038/sj.onc.1204944

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