Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis

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Title: Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis
Author: Lungu, Gina Florentina
Abstract: Here we studied the role of hypoxia and hypoxia -induced factors in the development of breast cancer brain metastasis by using ENU1564 , a carcinogen -induced mammary adenocarcinoma cell line . We detected hypoxia noninvasively by using a novel spectroscopic photoacoustic tomography technology (SPAT ) . Sprague -Dawley rats inoculated intracranially with ENU1564 , a carcinogen -induced rat mammary adenocarcinoma cell line , were imaged with SPAT three weeks post inoculation . Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain . We showed that HIF -1 ? , MMP -9 , VEGF -A , and VEGFR2 (Fkl -1 ) protein and mRNA expression levels were higher (P < 0 .05 ) in brain tumor tissues compared to normal brain . We also found an increased expression of HIF -1 ? proteins , MMP -9 , VEGF -A and VEGFR2 mRNA and proteins in hypoxic ENU1564 cells in vitro . We also demonstrated the involvement of PI3K -Akt pathway in hypoxic regulation of MMP -9 and VEGF but not VEGFR2 by using specific PI3K inhibitor . Using MEK1 /2 inhibitor we showed that hypoxic regulation of MMP -9 , VEGF -A and VEGFR2 also involve MEK1 /2 -ERK pathway . We also investigated the effect of fibroblast growth factor -1 (FGF -1 ) , one of the factors known to be upregulated by hypoxia , on the expression of MMP -9 in ENU1564 cell line . We observed that FGF -1 induces an increase in MMP -9 mRNA , protein , and activity in ENU1564 cells . Next , we investigated the role of components of PI3K -Akt and MEK1 /2 -ERK signaling pathways in our system . We demonstrated that FGF -1 increases Akt phosphorylation , triggers nuclear translocation of NF - ?Bp65 , and enhances degradation of cytoplasmic I ?B ? . Pretreatment of cells with LY294002 , a PI3K inhibitor , significantly inhibited MMP -9 protein expression in FGF -1 -treated cells . Conversely , our data showed that FGF -1 increases ERK phosphorylation in ENU1564 cells , increases c -jun and c -fos mRNA expression in a time -dependent manner , and triggers nuclear translocation of c -jun . Pretreatment of cells with PD98059 , a MEK1 /2 inhibitor significantly inhibited MMP -9 protein expression in FGF -1 treated cells . Finally , we observed increased DNA binding of NF - ?B and AP -1 in FGF -1 -treated cells and that mutation of either NF - ?B or AP -1 response elements prevented MMP -9 promoter activation by FGF -1 .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -3082
Date: 2009-05-15

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Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -3082 .

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