Splicing variant ΔVII-Ets1 is downregulated in invasive Ets1-expressing breast cancer cells

Ballschmieter, Pia; Braig, Melanie; Lindemann, Ralph K.; Nordheim, Alfred; Dittmer, Jürgen

doi:10.3892/ijo.22.4.849

Cited by 11 publications

(14 citation statements)

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“…Jurkat T cells were used as a positive control for Rho-GDIh. Note that Jurkat T cells also express a truncated form of Ets1, DVII-Ets1, which is missing in MDA-MB-231 cells (47). B, a second Ets1-specific siRNA (siE1#2 ) has the same effect as siE1 on Ets1 and Rho-GDIh RNA expression.…”

Section: Resultsmentioning

confidence: 97%

Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

et al. 2007

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Rho GDP dissociation inhibitor B (Rho-GDIB), an inhibitor of Rho GTPases, is primarily expressed by hematopoietic cells but is also found in epithelial cancer cells. Recently, we have identified Rho-GDIB as a target of the transcription factor Ets1. Here, we show that, in breast cancer cells, Ets1 regulates Rho-GDIB expression and binds to the upstream region of the Rho-GDIb gene. Furthermore, in primary breast cancer, Rho-GDIB is coexpressed with Ets1. Studying the function of Rho-GDIB in breast cancer, we found that a Rho-GDIB-specific small interfering RNA increased cellular migration but also decreased the expression of cyclooxygenase-2 (Cox-2) oncogene as shown by microarray, quantitative reverse transcription-PCR, and Western blot analyses. Further studies revealed that Rho-GDIB regulates Cox-2 gene at least partly on the transcriptional level, most likely by activating nuclear factor of activated T cells 1 (NFAT-1). Vav-1, an interaction partner of Rho-GDIB, was also found to interfere with Cox-2 expression and NFAT-1 cellular distribution, suggesting a cooperative action of Rho-GDIB and Vav-1 on Cox-2 expression. To explore the importance of Rho-GDIB for the survival of breast cancer patients, two cohorts, including 263 and 117 patients, were analyzed for clinical outcome in relation to Rho-GDIB RNA and protein levels, respectively. Expression of Rho-GDIB was not associated with either disease-free or overall survival in the two patient population. Our data suggest that the expression of Rho-GDIB in breast cancer is neither beneficial nor disadvantageous to the patient. This may be the net effect of two opposing activities of Rho-GDIB, one that suppresses tumor progression by inhibiting migration and the other that stimulates it by enhancing Cox-2 expression. [Cancer Res 2007;67(22):10694-702]

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Section: Resultsmentioning

confidence: 97%

Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

et al. 2007

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“…These distinctions are physiologically relevant; ectopic expression of the p42-Ets1 isoform but not the full-length p51-Ets1 isoform in DLD-1 colon cancer cells restores Fasmediated apoptosis (32). A similar proapoptotic role for the p42-Ets1 isoform has been suggested for MDA-MB-231 invasive breast cancer cells (3). While much work characterizing the functions of Ets1 has been done, relatively little is known about the interplay between the two protein isoforms in mediating these functions in vivo.…”

mentioning

confidence: 77%

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Higuchi

Bartel

Masuya³

et al. 2007

Molecular and Cellular Biology

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Ets1 is a member of the Ets transcription factor family. Alternative splicing of exon VII results in two naturally occurring protein isoforms: full-length Ets1 (p51-Ets1) and Ets1⌬VII (p42-Ets1). These isoforms bear key distinctions regarding protein-protein interactions, DNA binding kinetics, and transcriptional target specificity. Disruption of both Ets1 isoforms in mice results in the loss of detectable NK and NKT cell activity and defects in B and T lymphocytes. We generated mice that express only the Ets1 ⌬VII isoform. Ets1⌬VII homozygous mice express no p51-Ets1 and elevated levels of the p42-Ets1 protein relative to the wild type and display increased perinatal lethality, thymomegaly, and peripheral lymphopenia. Proliferation was increased in both the thymus and the spleen, while apoptosis was decreased in the thymus and increased in the spleen of homozygotes. Significant elevations of CD8 ؉ and CD8 ؉ CD4 ؉ thymocytes were observed. Lymphoid cell (CD19 ؉ , CD4 ؉ , and CD8 ؉ ) reductions were predominantly responsible for diminished spleen cellularity, with fewer memory cells and a failure of homeostatic proliferation to maintain peripheral lymphocytes. Collectively, the Ets1⌬VII mutants demonstrate lymphocyte maturation defects associated with misregulation of p16 Ink4a , p27Kip1 , and CD44. Thus, a balance in the differential regulation of Ets1 isoforms represents a potential mechanism in the control of lymphoid maturation and homeostasis.

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“…p42 is derived from an mRNA splice variant lacking exon VII and has previously been detected in both benign and malignant breast tumours (Behrens et al, 2001). In MDA-MB-231 breast cancer cells but not MCF-7 cells, overexpression of the p42 form of Ets-1 was found to reduce cell survival (Ballschmieter et al, 2003). On the other hand, in colon cancer cells, the p42 form of the Ets-1 protein was shown to rescue Fas-induced apoptosis (Li et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Ets-1 transcription factor in human breast cancer

et al. 2004

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The Ets family of transcription factors regulate expression of multiple genes involved in tumour progression. The aim of this study was to investigate the expression of Ets-1 in a large panel of human breast cancers and relate its levels to the parameters of tumour progression and metastasis. Using RT -PCR, Ets-1 mRNA was detected in 30 out of 42 (71%) fibroadenomas and 131 out of 179 (73%) primary breast carcinomas. Similarly, levels of Ets-1 mRNA were not significantly different in fibroadenomas and primary breast carcinomas. Using Western blotting, four forms of the Ets-1 protein were detected, that is, p33, p42, p51 and p52. Levels of both p51 and p52 but not p33 and p42 were present at significantly higher levels in the carcinomas compared to the fibroadenomas (for p51, Po0.007; for p52, Po0.02; Mann -Whitney U-test). Levels of p52, p51 and p33 correlated significantly with uPA protein levels (Po0.01), while only levels of p52 correlated significantly with HER-2/neu protein levels (Po0.01). Using immunohistochemistry, Ets-1 was found predominantly in tumour cells, but was also detected in some stromal cells surrounding tumour islands. We conclude that, while at the mRNA level, Ets-1 was found at similar levels in fibroadenomas and primary breast carcinomas, higher protein levels were detected in the cancers compared to the benign specimens. Since p52, p51 and p33 correlate with uPA levels, these forms of Ets-1 may play a role in breast cancer metastasis.

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Splicing variant ΔVII-Ets1 is downregulated in invasive Ets1-expressing breast cancer cells

Cited by 11 publications

References 0 publications

Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Cyclooxygenase-2 Is a Target Gene of Rho GDP Dissociation Inhibitor β in Breast Cancer Cells

Thymomegaly, Microsplenia, and Defective Homeostatic Proliferation of Peripheral Lymphocytes in p51-Ets1 Isoform-Specific Null Mice

Overexpression of the Ets-1 transcription factor in human breast cancer

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