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Title: The relationship between metastasis-inducing S100 proteins (MIPs) and matrix metalloproteinases (MMPs) in rat and human breast cancer
Author: Al-Medhtiy, M. H.
ISNI:       0000 0004 7658 468X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Breast cancer metastasis is the most common cause of death amongst females worldwide. The presence of metastasis-inducing proteins such as S100P or S100A4 in primary breast tumours has been reported to be associated with a reduction in patient survival times in vivo and these proteins enhanced cell migration and invasion in vitro as well. However, the pathway of S100P/A4 in inducing metastasis or cell migration/invasion is still controversial and not clear. To investigate the role of matrix metalloproteinases as mediators of S100P/A4-stimulated cell migration/invasion, human HeLa and rat mammary 37 (R37) and S100P/A4 overexpressing cell lines (R37-S100P/A4) were used to demonstrate levels and activities of matrix metalloproteinases (MMPs) using antibody arrays, zymography and Western blots. siRNAs to specific MMPs and direct addition of S100 proteins were used to measure effects on cell migration and invasion. Primary tumours from 183 breast cancer patients were immunohistochemically stained to investigate the association between MMPs and S100 proteins and their effect on patients' survival times using relative association and Cox's multivariate regression analysis. In vitro, R37-S100P/A4 cells significantly (P=0.035) produced only MMP-2, -9 and -13. In addition, MMP-2 and MMP-13 showed significant (Student's t-test, P=0.031) proteinase activity (active and pro forms) on specific substrates, but MMP-9 showed only the inactive proform. Knock-down of each MMP significantly reduced R37- S100P/A4 cell migration and invasion (P=0.037). Extracellular additions of S100P/A4 to R37 cells caused significant increases in these same MMPs (P=0.026) and in cell migration and invasion (P=0.025). RAGE receptor levels were expressed significantly higher in invasive carcinoma R37-S100P/A4 cells compared to control R37 cells. When the RAGE receptor was inhibited, it caused a significant reduction in R37-S100P/A4 (P=0.037) or S100P/A4-treated R37 wt cell (P=0.007) invasion. In vivo, the presence of one of S100P, S100A4, MMP-2, MMP-9 and MMP-13 showed significant reduction in patients' survival times. There was a strong association between MMPs and S100P/S100A4 and both S100 proteins partially confounded the MMPs effect on patients' survival times and death-risk. Since manipulation of the levels of S100P/A4 and the three MMPs caused changes in cell migration/invasion, the three MMPs are probably some of the S100 downstream effectors, particularly for cell invasion. Moreover, there was more association of one S100 protein with a particular MMP in cultured cells and in human breast tumours, suggesting that different S100 proteins are likely to promote selective enhancement of individual MMPs. This conclusion may explain the observed synergistic effect (Wang et al., 2006) of the combination of S100P and S100A4 on early patient demise in breast cancer.
Supervisor: Rudland, Philip ; Barraclough, Roger Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral