Abstract |
Transforming growth factor beta 1 (TGF-beta1) is a potent tumor suppressor but, paradoxically, TGF-beta1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-beta type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-beta signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinase-inactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/ gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-beta-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-beta-mediated cell migration. Collectively, our results show that TGF-beta-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.
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Authors | A Safina, E Vandette, A V Bakin |
Journal | Oncogene
(Oncogene)
Vol. 26
Issue 17
Pg. 2407-22
(Apr 12 2007)
ISSN: 0950-9232 [Print] England |
PMID | 17072348
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Receptors, Transforming Growth Factor beta
- Transforming Growth Factor beta1
- Protein Serine-Threonine Kinases
- Activin Receptors, Type I
- Receptor, Transforming Growth Factor-beta Type I
- TGFBR1 protein, human
- Tgfbr1 protein, mouse
- Matrix Metalloproteinase 9
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Topics |
- Activin Receptors, Type I
(physiology)
- Animals
- Breast Neoplasms
(blood supply, enzymology, pathology)
- Enzyme Activation
(physiology)
- Female
- Humans
- Matrix Metalloproteinase 9
(biosynthesis, genetics)
- Mice
- Mice, SCID
- Neoplasm Invasiveness
- Neovascularization, Pathologic
(enzymology)
- Protein Serine-Threonine Kinases
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta
(physiology)
- Signal Transduction
(physiology)
- Transforming Growth Factor beta1
(physiology)
- Up-Regulation
(physiology)
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