Role for TIMP-1 in Breast Cancer Progression

摘要

In order to assess the role of TIMP-1 in breast cancer development, we created several MCF-7 and MDA-MB-231 cell lines which overexpress TIMP-1 as well as MDA-MB-231 cells which underexpress TIMP-1 using shRNA. Compared to vector control cells, MCF-7 TIMP-1(+), MDA-MB-231 TIMP-1(+) cells and MDA-MB- 231 (-) cells displayed no change in proliferation, and these cells did not demonstrate activation of the p38, ERK, AKT or FAK signaling pathways. Additionally, exogenously supplied TIMP-1 did not activate these signaling pathways in either MCF-7 or MCF10A cells, contrary to published reports. Also, TIMP-1 overexpression inhibited MCF-7 motility in modified Boyden Chamber assays, whereas no differences in invasion were observed in MDA-MB-231 (-) cells compared to vector controls. In vivo xenograft studies in SCID/bg mice revealed that TIMP-1 was able to stimulate tumorigenesis of MCF-7 cells, potentially by stimulating angiogenesis as noted by the increase in CD34 positive blood vessels. No differences in tumor growth were observed with MDA- MB-231 TIMP-1 shRNA cells compared to control cells. Finally, Affymetrix array analysis revealed that TIMP-1 overexpression did have an effect on gene expression in MCF-7 and MDA-MB-231 cells.