Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo

Ghadersohi, Ali; Pan, Dalin; Fayazi, Zahra; Hicks, David G.; Winston, Janet S.; Li, Fengzhi

doi:10.1007/s10549-006-9314-9

Cited by 47 publications

(91 citation statements)

References 19 publications

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“…As reported earlier, PDEF protein detection did not always correspond to PDEF mRNA levels. Although some studies showed increased PDEF mRNA (Turcotte et al, 2007) or protein expression in invasive ductal carcinoma (Sood et al, 2007) others observed reduced protein expression in breast cancer cells (Feldman et al, 2003;Doane et al, 2006;Ghadersohi et al, 2007;Turner et al, 2008). Recently, this discrepancy was explained by the identification of two microRNAs in human breast tumour samples that directly repressed PDEF protein expression in spite of the detection of high PDEF mRNA concentration .…”

Section: Discussionmentioning

confidence: 99%

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Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

et al. 2010

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BACKGROUND: LIM and SH3 protein 1 (LASP-1) is a nucleo-cytoplasmatic signalling protein involved in cell proliferation and migration and is upregulated in breast cancer in vitro studies have shown that LASP-1 might be regulated by prostate-derived ETS factor (PDEF), p53 and/or LASP1 gene amplification. This current study analysed the prognostic significance of LASP-1 on overall survival (OS) in 177 breast cancer patients and addressed the suggested mechanisms of LASP-1-regulation. METHODS: Nucleo-cytoplasmatic LASP-1-positivity of breast carcinoma samples was correlated with long-term survival, clinicopathological parameters, Ki67-positivity and PDEF expression. Rate of LASP1 amplification was determined in micro-dissected primary breast cancer cells using quantitative RT -PCR. Cell-phase dependency of nuclear LASP-1-localisation was studied in synchronised cells. In addition, LASP-1, PDEF and p53 expression was compared in cell lines of different tumour entities to define principles for LASP-1-regulation. RESULTS: We showed that LASP-1 overexpression is not due to LASP1 gene amplification. Moreover, no correlation between p53-mutations or PDEF-expression and LASP-1-status was observed. However, nuclear LASP-1-localisation in breast carcinomas is increased during proliferation with peak in G2/M-phase and correlated significantly with Ki67-positivity and poor OS. CONCLUSION: Our results provide evidence that nuclear LASP-1-positivity may serve as a negative prognostic indicator for long-term survival of breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

“…In invasive breast cancer cells, LASP-1-expression was significantly inversely affected by prostate-derived ETS factor (PDEF), a transcription factor known to repress a variety of genes that are possibly involved in oncogenesis, such as the apoptosis regulator survivin (Ghadersohi et al, 2007) and the pro-invasive protease uPA .…”

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confidence: 99%

Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

et al. 2010

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“…Subsequent studies, however, reported loss of PDEF protein expression in the progression from benign breast and prostate tissues to carcinomas (19)(20)(21). The present study, for the first time, shows frequent increased expression of PDEF protein in both breast and prostate tumors and these results differ from the conclusions of previous reports (19)(20)(21). A potential explanation for differing results in previous studies versus this study may be the small sample sizes analyzed in those studies.…”

Section: Discussionmentioning

confidence: 99%

“…The latter potential stems from: i) the high degree of sequence homology approaching 45 to 55% amino acid sequence identity in the DNA binding domain between PDEF and other Ets factors (11); and ii) the large number of Ets factors that are expressed in normal mammary gland, and several at much higher levels than Pse or PDEF (17,22). The third study (21) used antibody raised against the same N-terminal segment of PDEF as used in this study, however, the specificity of the immunohistochemical assay for PDEF was not demonstrated in that study. The specificity of our antibody for PDEF was demonstrated rigorously in the experiments shown in Figures 1 and 2 and our results are based on the analysis of a large number of samples.…”

Section: Discussionmentioning

confidence: 99%

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression

et al. 2007

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The purpose of this study was to understand the characteristics of PDEF protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays including benign prostate, prostate intra-epithelial neoplasias and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46% and 51% of benign breast tissues, intraductal, invasive ductal and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast versus tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu over expression. Increased expression of PDEF was also found in 27%, 33% and 40% of benign prostate tissues, PIN samples and prostate adenocarcinomas, respectively. Again, in matching samples of cancer versus benign and cancer versus PIN, 68% and 70% respectively showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared to low grade tumors (P<0.01). Additionally, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.

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“…At present, apart from surgical resection of the tumor, radiation therapy is generally used for treatment of meningiomas and other alternative treatments are under trial. In recent years, the RNAi-mediated approach has emerged as a promising schema for the treatment of various in vivo disease models (38). Our investigation uses this approach to examine the therapeutic significance of RNAi-mediated downregulation of cathepsin B and MMP-9 in malignant meningiomas.…”

Section: Discussionmentioning

confidence: 99%

RNAi-mediated abrogation of cathepsin B and MMP-9 gene expression in a malignant meningioma cell line leads to decreased tumor growth, invasion and angiogenesis

et al. 2007

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Abstract. Malignant meningiomas are highly aggressive and frequently recur after surgical resection of the tumor. Earlier studies have reported that the cysteine protease cathepsin B and the matrix metalloproteinase MMP-9 play important roles in tumor progression. In the present study, we made an attempt to evaluate the roles of these proteases in the malignant meningioma tumor microenvironment and determined the effectiveness of using single or bicistronic siRNA constructs for cathepsin B and MMP-9, in both in vitro and in vivo models. Transfection of a plasmid vector expressing doublestranded RNA for cathepsin B and MMP-9 significantly inhibited mRNA and protein levels of cathepsin B and MMP-9. The migration and invasion of meningioma cells were decreased after treatment with single or bicistronic siRNA constructs for cathepsin B and MMP-9 compared to controls and vector controls. Inhibition of angiogenesis was observed when the cells were transfected with single or bicistronic constructs for cathepsin B and MMP-9, when compared to controls or empty vector controls. Our study revealed that abrogation of cathepsin B and MMP-9 expression decreased the activation of major proteins involved in MAP kinase and PI3 kinase pathways indicating that targeting these proteases may hinder intracellular signaling and thus decrease cell survival and proliferation in malignant meningiomas. In addition to the in vitro evidence, we observed a significant regression of pre-established orthotopic tumors after treatment with RNAi plasmid vectors targeting cathepsin B and MMP-9. Furthermore, these observations demonstrate that the simultaneous RNAi-mediated targeting of cathepsin B and MMP-9 has potential application for the treatment of human meningiomas.

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Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo

Cited by 47 publications

References 19 publications

Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression

RNAi-mediated abrogation of cathepsin B and MMP-9 gene expression in a malignant meningioma cell line leads to decreased tumor growth, invasion and angiogenesis

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