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- Title
- IDENTIFICATION OF EPITHELIAL STROMAL INTERACTION 1 AND EPIDERMAL GROWTH FACTOR RECEPTOR AS NOVEL KR(&)#220;PPEL-LIKE FACTOR 8 TARGETS IN PROMOTING BREAST CANCER PROGRESSION.
- Creator
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Li, Tianshu, Zhao, Jihe, Khaled, Annette, Altomare, Deborah, Lambert, Stephen, University of Central Florida
- Abstract / Description
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Breast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast...
Show moreBreast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast-induced gene in non-invasive breast cancer cells and epidermal growth factor receptor (EGFR) are highly overexpressed in aggressively invasive breast carcinomas including triple negative breast cancers. In this thesis project, we demonstrate high co-overexpression of KLF8 with EPSTI1 as well as EGFR in invasive breast cancer cells and patient tumors. We also show that KLF8 upregulates the expression of EPSTI1 by directly binding and activating the EPSTI1 gene promoter, and KLF8 upregulates the expression of EGFR not only by directly activating the EGFR gene promoter but also by preventing EGFR translation from microRNA141-dependent inhibition. Genetic, signaling and animal cancer model analyses indicate that downstream of KLF8, EPSTI1 promotes the tumor invasion and metastasis by activating NF-?B through binding valosin containing protein (VCP) and subsequent degradation of I?B?, whereas EGFR promotes tumor growth and metastasis via activation of ERK. Taken together, these data identify EPSTI1 and EGFR as novel KLF8 targets in breast cancer and suggest that KLF8 may be targeted for new effective treatment of breast cancer.
Show less - Date Issued
- 2013
- Identifier
- CFE0005366, ucf:50474
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0005366
- Title
- LIM KINASE 1 MODULATES EXPRESSION OF MATRIX METALLOPROTEINASES AND ASSOCIATES WITH GAMMA-TUBULIN: DUAL ROLE IN INVASION AND MITOTIC PROCESSES.
- Creator
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Tapia, Tenekua, Chakrabarti, Ratna, University of Central Florida
- Abstract / Description
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LIM kinase 1 (LIMK1) is a unique dual specificity serine/threonine kinase containing two N-terminal LIM domains in tandem, a PDZ domain and a C-terminal catalytic domain. LIMK1 is involved in modulation of actin cytoskeleton through inactivating phosphorylation of the ADF (actin depolymerization factor) family protein cofilin. Recent studies have shown that LIMK1 is upregulated in breast and prostate cancer cells and tissues, promotes metastasis in animals and induces acquisition of an...
Show moreLIM kinase 1 (LIMK1) is a unique dual specificity serine/threonine kinase containing two N-terminal LIM domains in tandem, a PDZ domain and a C-terminal catalytic domain. LIMK1 is involved in modulation of actin cytoskeleton through inactivating phosphorylation of the ADF (actin depolymerization factor) family protein cofilin. Recent studies have shown that LIMK1 is upregulated in breast and prostate cancer cells and tissues, promotes metastasis in animals and induces acquisition of an invasive phenotype when ectopically expressed in benign prostate epithelial (BPH) cells. Furthermore, overexpression of LIMK1 was associated with altered sub cellular localization of the membrane type 1 matrix metalloprotease (MT1-MMP). Matrix metalloproteases (MMPs) are a family of zinc dependant proteolytic enzymes that hydrolyze extra cellular matrix and cell surface molecules. A number of MMPs including MMP-2, MMP-9 and their activator MT1-MMP are over expressed in a variety of cancers including prostate cancer. The abundant expression of these enzymes contributes to changes in the tumor microenvironment, which facilitate degradation of the surrounding collagen matrix and migration of cells through the matrix defects. In this study, we show that MMPs are involved in LIMK1 induced invasion of otherwise non-invasive BPH cells. We also show that (a) the kinase activity of LIMK is not essential for the invasive behavior of the cells and (b) the absence of LIM domains significantly retards cell invasion. We have established transfected sub lines of BPH cells stably expressing 1) constitutively active LIMK1 (BPHLCA), 2) kinase dead LIMK1 (BPHLKD) and 3) only the kinase domain of LIMK1 (BPHLK) for our study. In vitro invasion assays revealed that LIMK1 induced invasion was inhibited by the MMP specific inhibitor, GM6001, and that cells expressing kinase-dead LIMK1 were equally invasive. Furthermore, BPH cells expressing LIMK1 mutants expressed higher amounts of MMP-2 and MMP-9. Substrate zymography revealed increased concentration of secreted MMP-2 and MMP-9 in the media of BPHLCA and BPHLK cells respectively compared to BPHV (vector control) cells. Quantitative RT-PCR also showed a ~10 fold increase in the steady state concentration of MMP-2 in BPHLCA cells compared to the control BPHLV cells. Expression of active LIMK1 stimulated cell-surface expression of MT1-MMP in BPHLCA cells as determined by flow cytometry. A modest increase in expression of MT1-MMP was noted in BPHLKD cells compared to BPHLK and BPHV cells. Immunoflourescence analysis indicated differential localization of MT1-MMP and LIMK1 in BPH cells expressing different mutants of LIMK1. Co-localization of LIMK1 and MT1-MMP in the plasma membrane and in the perinuclear region was also evident in these cells. Furthermore, here we provide evidence that suggests a functional role for phosphorylated (activated) LIMK1/2 (p-LIMK1/2) during mitosis through its association with γ-tubulin. Immunoflourescence analysis showed distinct co-localization of γ -tubulin and p-LIMK1/2 in the centrosomes during mitosis from early prophase to the beginning of telophase. No association was seen in the interphase or in late telophase. Phospho-LIMK1/2 was co-precipitated in immunoprecipitates of γ -tubulin using an anti- γ -tubulin antibody suggesting a physical association between these proteins in a complex. This finding reveals a novel role of LIMK1 in the mitotic process. In summary, our data suggests that MMPs are involved in LIMK1 induced invasion of prostate epithelial cells, and that this effect is mediated through altered expression and activation of specific MMPs. Furthermore, LIMK1 induced invasion is dependant on the presence of LIM domains more than the kinase activity. Finally, we show that phosphorylated LIMK1 and LIMK2 are involved in the mitotic process in a stage specific manner through its association with the centrosomal protein γ -tubulin. Because LIMK1 promotes invasion in vitro, regulates expression of MMPs, and is involved in mitotic processes, it is an attractive drug target for prostate cancer therapy.
Show less - Date Issued
- 2007
- Identifier
- CFE0001812, ucf:47361
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0001812
