The Epithelial-Specific ETS Transcription Factor ESX/ESE-1/Elf-3 Modulates Breast Cancer-Associated Gene Expression

Eckel, Kristin L.; Tentler, John J.; Cappetta, Gerald J.; Diamond, Scott E.; Gutierrez‐Hartmann, Arthur

doi:10.1089/104454903321515896

Cited by 50 publications

(70 citation statements)

References 43 publications

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“…17,18 Elf3 was shown to be sufficient to transform normal breast epithelial cells 19 and markedly increase their survival. 20 Overexpression of Pdef has been found to stimulate cell mobility and invasion. 21 Based on these observations, it is generally thought that Ets proteins possess oncogenic properties.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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“…57 It has also been shown that ESE-1 is able to activate several malignancy-associated gene promoters, including the Her2/Neu (ErbB-2) promoter, and that ESE-1 expression is required for cellular survival of both non-transformed MCF-12A and transformed T47D human mammary epithelial cells in colony formation assays. 58 Therefore, a positive feedback loop with both ErbB-2 and ESE-1 is believed to occur based on the observations of increased ESE-1 expression in response to Her2/Neu receptor activation and ESE-1 subsequently binding and activating the Her2/Neu gene promoter. Moreover, it has also been reported that ESE-1 and ErbB-2 can cooperate to confer an invasive phenotype in human mammary epithelial cells.…”

Section: Ese-1 In Mammary Gland Development and Breast Cancermentioning

confidence: 99%

Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

Oliver

Kushwah

2012

Laboratory Investigation

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The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epitheliumspecific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases. KEYWORDS: cancer; development; epithelial cell differentiation; ESE-1; ETS transcription factor; inflammation; regeneration The E26 transformation-specific (ETS) family of transcription factors is characterized by a highly conserved 84-aminoacid DNA-binding domain, known as the ETS domain. 1 Because the first member of the ETS family, the v-ets oncogene, was originally discovered as part of a fusion protein with gag and myb expressed by the E26 avian erythroblastosis-transforming retrovirus and its DNA-binding domain is E26 transformation-specific, this 84-amino-acid DNA-binding domain was named the ETS domain. 1 The ETS domain is usually located within the carboxyl-terminal region of the protein as a winged helix-turn-helix structural motif and mediates binding to sites of purine-rich DNA, commonly containing a core consensus sequence of GGAA/T, within the promoter and enhancer regions of target genes. 2,3 Many ETS transcription factors also contain a pointed domain, which is located within the amino-terminal region and is involved in protein-protein interactions. 2 Approximately 30 members of the ETS transcription factor family have been identified in mammals (ie 27 in humans and 26 in mice), 4 and have been shown to play crucial roles in the regulation of many physiological and pathological processes, such as embryonic develo...

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“…42 The ETS family of transcription factors contributes to tumorigenesis in many different tissues, including breast epithelium; an epithelium-specific Ets member (ESX) is particularly relevant to breast cancer, its expression being required for cellular survival of nontransformed MCF-12A and transformed T47D human mammary cells. 43 The ETS domain family of transcription factors is found in the promoters of the MMP family of matrix-degrading enzymes and is important in the angiogenesis and metastasis of cancers. 44 The decreased expression of MMP7 and ETS transcription factors in treated cells suggested that tanshinone IIA could inhibit the invasive and metastatic potential of cancer.…”

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confidence: 99%

Potential anticancer activity of tanshinone IIA against human breast cancer

et al. 2005

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Tanshinone IIA is a derivative of phenanthrene-quinone isolated from Danshen, a widely used Chinese herbal medicine. It has antioxidant properties and cytotoxic activity against multiple human cancer cell lines, inducing apoptosis and differentiation of some human cancer cell lines. Our purpose was to confirm its anticancer activity on human breast cancer in vitro and in vivo and to elucidate the mechanism of its activity. Human breast cancer cells were tested in vitro for cytotoxicity, colony formation inhibition, BrdU incorporation and gene expression profiling after treatment with tanshinone IIA. Seven nude mice bearing human breast infiltrating duct carcinoma orthotopically were tested for anticancer activity and expression of caspase-3 in vivo by s.c. injection of tanshinone IIA at a dose of 30 mg/kg 3 times/week for 10 weeks. Tanshinone IIA demonstrated a dose-and time-dependent inhibitory effect on cell growth (IC 50 = 0.25 mg/ml), and it significantly inhibited colony formation and BrdU incorporation of human breast cancer cells. Oligonucleotide microarray analysis identified 41 upregulated (1.22%) and 24 downregulated (0.71%) genes after tanshinone IIA treatment. Upregulated genes were involved predominantly in cycle regulation, cell proliferation, apoptosis, signal transduction and transcriptional regulation; and downregulated genes were associated mainly with apoptosis and extracellular matrix/adhesion molecules. A 44.91% tumor mass volume reduction and significant increase of casepase-3 protein expression were observed in vivo. Our findings suggest that tanshinone IIA might have potential anticancer activity on both ER-positive and -negative breast cancers, which could be attributed in part to its inhibition of proliferation and apoptosis induction of cancer cells through upregulation and downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis, signal transduction, transcriptional regulation, angiogenesis, invasive potential and metastatic potential of cancer cells. ADPRTL1 might be the main target at which tanshinone IIA acted. ' 2005 Wiley-Liss, Inc.Key words: tanshinone IIA; anticancer activity; breast cancer; growth inhibition; apoptosis Breast cancer is a major public health problem in the United States and in most industrialized countries.1 It is the most common cancer in women and the leading cause of cancer death among women 35-54 years of age.2 The rising incidence and poor prognosis of breast cancer cases have prompted a search for additional preventive and therapeutic modalities.Danshen (Salvia miltiorrhiza Bunge) is a widely used Chinese herbal medicine; its extracts contain diterpene quinone and phenolic acid derivatives, including tanshinone (I, IIA and IIB), cryptotanshinone, isocryptotanshinone, miltirone, tanshinol (I and II) and salviol. These compounds have antioxidant properties and protect against lipid peroxidation in vitro and in vivo, making them potential antidotes for free radical-based disorders.3-5 Tanshinone IIA is a derivative of...

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The Epithelial-Specific ETS Transcription Factor ESX/ESE-1/Elf-3 Modulates Breast Cancer-Associated Gene Expression

Cited by 50 publications

References 43 publications

Profile of Ets gene expression in human breast carcinoma

Profile of Ets gene expression in human breast carcinoma

Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

Potential anticancer activity of tanshinone IIA against human breast cancer

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