Expression of the transcription factor Ets-1 is an independent prognostic marker for relapse-free survival in breast cancer

Span, Paul N.; Manders, Peggy; Heuvel, J. J. T. M.; Thomas, Chris M.G.; Bosch, Remko R.; Beex, L.V.A.M.; Sweep, Fred C.G.J.

doi:10.1038/sj.onc.1206040

Cited by 119 publications

(108 citation statements)

References 18 publications

(16 reference statements)

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“…For example, Ets1 and Ets2 expression was reportedly elevated in breast tumors. [25][26][27] However, we identified no consistent change in the Ets2 transcript level and found that the Ets1 transcript level was instead lower in breast cancer cells than in normal breast epithelial cells. We showed that this decreased Ets1 expression occurred not only in cell lines, but also in primary breast cancers (Fig.…”

Section: Discussionmentioning

confidence: 54%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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Background: Ets genes encode a family of transcription factors that play key roles in cell proliferation, differentiation and apoptosis. Fusions of Ets genes with other targets have been described in Ewing's sarcoma, chronic myelomonocytic leukemia and more recently prostate carcinoma. Ets expression in breast carcinoma has not been comprehensively studied, and is the focus of this study.Methods: RT-Q-PCR was used to determine the expression of Ets genes in a panel of ten common breast cancer cell lines, two immortalized normal breast epithelial cell lines, and one primary culture of human mammary epithelial cells. Ets with altered expression in cancer cell lines were verified in primary breast tumors.Results: Transcripts of 21 of the 27 Ets genes were detected in either normal or cancer cells. Of the 21 detectable genes, 14 were expressed at a similar level in both normal and breast cancer cell lines. Four genes, Ehf, Elf3, Elf5 and Pdef, were expressed at higher levels in breast cancer cells than normal epithelials. Surprisingly, the expression of Elk3, Ets1 and Fli1 was repressed in breast cancer cells. The protein status of Ehf, Elf3, Pdef, Elk3, Ets1 and Fli1, strongly correlated with the transcript data, suggesting that Ets expression is regulated primarily at the transcriptional level. Similarly, Elf3, Pdef and Tel2 were overexpressed, while Elk3, Ets1 and Fli1 were under-expressed in primary breast tumor specimens in comparison with normal mammary tissues.Conclusions: Our study identified a subset of Ets genes with altered expression in breast carcinoma, implicating their roles in mammary tumorigenesis. While the Ets overexpression pattern is useful to uncover recurrent genetic alterations involving Ets genes, the repressed expression of several Ets genes suggests that some Ets proteins may play suppressor roles during breast cancer progression. Our results warrant detailed studies of individual Ets activity during mammary gland neoplasia.

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Section: Discussionmentioning

confidence: 54%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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“…1,2 In this assay, it is mandatory to relate gene expression to the amount of tissue analyzed, that is, to normalize for optimal comparison of expression levels between tissue samples. Inaccurate normalization results in inadequate quantification and spurious conclusions.…”

mentioning

confidence: 99%

Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes

Kok

Roelofs

Giesendorf

et al. 2005

Laboratory Investigation

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For interpretation of quantitative gene expression measurements in clinical tumor samples, a normalizer is necessary to correct expression data for differences in cellular input, RNA quality, and RT efficiency between samples. In many studies, a single housekeeping gene is used for normalization. However, no unequivocal single reference gene (with proven invariable expression between cells) has been identified yet. As the best alternative, the mean expression of multiple housekeeping genes can be used for normalization. In this study, no attempt was made to determine the gold-standard gene for normalization, but to identify the best single housekeeping gene that could accurately replace the measurement of multiple genes. Expression patterns of 13 frequently used housekeeping genes were determined in 80 normal and tumor samples from colorectal, breast, prostate, skin, and bladder tissues with real-time quantitative RT-PCR. These genes included, large ribosomal protein, b-actin, cyclophilin A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerokinase 1, b-2-microglobin, b-glucuronidase, hypoxanthine ribosyltransferase (HPRT), TATA-box-binding protein, transferrin receptor, porphobilinogen deaminase, ATP synthase 6, and 18S ribosomal RNA. Principal component analysis was used to analyze these expression patterns, independent of the level of expression. Our approach identified HPRT as the single best reference gene that could be used as an accurate and economic alternative for the measurement of multiple housekeeping genes. We recommend this gene for future studies to standardize gene expression measurements in cancer research and tumor diagnostics until a definite gold standard has been determined.

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“…C‐ets‐1 overexpression has been shown to strongly promote malignant invasiveness of breast cancer cells, which is in line with our findings (Furlan et al ., 2008). Further, it is prognostic marker for poor prognosis of human breast cancer (Span et al ., 2002). The second mechanism of MET regulation by TGFβ1 is related to suppression of miR‐128‐3p which, in turn, directly targets MET , which is in line with Jiang and colleagues non‐small cell lung cancer (Jiang et al ., 2016), and thereby impairs HGF/MET‐mediated cell migration.…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

et al. 2018

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Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal‐like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal‐like breast cancer cell lines, as well as in triple‐negative breast cancer tumor tissues, compared to other subtypes. Using real‐time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)‐induced and MET‐dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C‐ets‐1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1‐induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR‐128‐3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR‐128‐3p reduced MET expression and abrogated HGF‐induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF‐induced and MET‐mediated cell migration, through positive regulation of C‐ets‐1 and negative regulation of miR‐128‐3p expression in basal‐like breast cancer cell lines and in triple‐negative breast cancer tissue.

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Expression of the transcription factor Ets-1 is an independent prognostic marker for relapse-free survival in breast cancer

Cited by 119 publications

References 18 publications

Profile of Ets gene expression in human breast carcinoma

Profile of Ets gene expression in human breast carcinoma

Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

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