TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro

被引:57
|
作者
Bigelow, Rebecca L. H. [1 ,2 ]
Williams, Briana J. [2 ,3 ]
Carroll, Jennifer L. [2 ,3 ]
Daves, Lisa K. [2 ,3 ]
Cardelli, James A. [1 ,2 ]
机构
[1] Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol & Immunol, Shreveport, LA 71130 USA
[2] Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Shreveport, LA 71130 USA
[3] Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA
关键词
TIMP-1; MDA-MB-231; cDNA array analysis; Xenografts; TISSUE INHIBITOR; GROWTH-FACTOR; METALLOPROTEINASES-1; TIMP-1; MATRIX METALLOPROTEINASES; EPITHELIAL-CELLS; MICROVESSEL DENSITY; CHALKLEY COUNT; ANGIOGENESIS; METASTASIS; PROGNOSIS;
D O I
10.1007/s10549-008-0170-7
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
TIMP-1 (Tissue inhibitor of matrix metalloproteinase-1) is typically associated with inhibition of matrix metalloproteinases (MMP) induced invasion. However, TIMP-1 is overexpressed in many malignancies and is associated with poor prognosis in breast cancer. The mechanisms by which TIMP-1 promotes tumorigenesis are unclear. Reduced levels of TIMP-1 mediated by shRNA in MDA-MB-231 breast cancer cells had no effect on cellular physiology in vitro or tumor growth in SCID mice compared to vector control MDA-MB-231 cells. However, overexpression of TIMP-1 in MDA-MB-231 cells resulted in inhibition of cell invasion and enhanced phosphorylation of p38 MAPK and AKT in vitro. Additionally, treatment of parental MDA-MB-231 cells with purified TIMP-1 protein led to activation of p38 MAPK and MKK 3/6. cDNA array analysis demonstrated that high expression of TIMP-1 in MDA-MB-231 cells resulted in alterations in expression of approximately 200 genes, 1.5 fold or greater compared to vector control cells (P < 0.1). Real-time RT-PCR confirmed changes in expression of several genes associated with cancer progression including DAPK1, FGFR4 and MAPK13. In vivo, high TIMP-1 expression induced tumor growth in SCID mice compared to vector control cells and increased tumor vessel density. Affymetrix array analysis of vector control and TIMP-1 MDA-MB-231 xenograft tumors revealed that TIMP-1 altered expression of approximately 600 genes in vivo, including MMP1, MMP13, S100A14, S100P, Rab25 and ID4. These combined observations suggest that the effects of TIMP-1 differ significantly in a 2-D environment compared to the 3-D environment and that TIMP-1 stimulates tumor growth.
引用
收藏
页码:31 / 44
页数:14
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