The ETS Transcription Factor ESE-1 Transforms MCF-12A Human Mammary Epithelial Cells via a Novel Cytoplasmic Mechanism

Prescott, Jason D.; Koto, Karen; Singh, Meenakshi; Gutierrez‐Hartmann, Arthur

doi:10.1128/mcb.24.12.5548-5564.2004

Cited by 58 publications

(104 citation statements)

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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.…”

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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“…Interestingly, overexpression of another family member, PEA3, induces branching morphogenesis in TAC-2 MECs, revealing a level of phenotypic specificity that suggests each factor may promote the transcription of a distinct set of target genes (52). Furthermore, according to a recent study, the transforming effects of ESE-1 involve a novel cytoplasmic function independent of its transcriptional activity, suggesting an additional level of complexity to the activities of Ets family proteins (53).…”

Section: Transcription Factorsmentioning

confidence: 99%

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

Shaw

Wrobel

Brugge

2004

J Mammary Gland Biol Neoplasia

137

117

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The development of breast carcinomas involves a complex set of phenotypic alterations in breast epithelial cells and the surrounding microenvironment. While traditional transformation assays provide models for investigating certain aspects of the cellular processes associated with tumor initiation and progression, they do not model alterations in tissue architecture that are critically involved in tumor development. In this review, we provide examples of how three-dimensional (3D) cell culture models can be utilized to dissect the pathways involved in the development of mammary epithelial structures and to elucidate the mechanisms responsible for oncogene-induced phenotypic alterations in epithelial behavior and architecture. Many normal mammary epithelial cell lines undergo a stereotypic morphogenetic process when grown in the presence of exogenous matrix proteins. This 3D morphogenesis culminates in the formation of well-organized, polarized spheroids, and/or tubules that are highly reminiscent of normal glandular architecture. In contrast, transformed cell lines isolated from mammary tumors exhibit significant deviations from normal epithelial behavior in 3D culture. We describe the use of 3D models as a method for both reconstructing and deconstructing the cell biological and biochemical events involved in mammary neoplasia.Keywords mammary epithelial cells; breast cancer; morphogenesis; 3D cell culture; oncogenesis Abbreviations used3D; three-dimensional; BARD-1, BRCA-1 associated ring domain; CDK, cyclin-dependent kinase; CGH, comparative genomic hybridization; CSF-1, colony-stimulating factor; CSF-1R, colonystimulating factor receptor; DCIS, ductal carcinoma in situ; E7, human papilloma virus 16 E7 protein; ECM, extracellular matrix; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EHS, Engelbreth-Holm-Swarm; EMT, epithelial-to-mesenchymal transition; ER, estrogen receptor; GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL-1, interleukin-1; MAPK, mitogen-activated protein kinase; MEC, mammary epithelial cell; MMP, matrix metalloproteinase; MMTV, mouse mammary tumor virus; PI3K, phosphotidylinositol-3 kinase; PR, progesterone receptor; Rb, retinoblastoma protein; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor 2 To whom correspondence should be addressed at Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115; e-mail: joan brugge@hms.harvard.edu.. 3 These authors contributed equally to this review. NIH Public AccessAuthor Manuscript J Mammary Gland Biol Neoplasia. Author manuscript; available in PMC 2006 July 17. FROM SOFT AGAR TO BASEMENT MEMBRANE GELS: MODELING MAMMARY TUMORIGENESIS IN VITROThe mammary gland is a complex organ, comprised of multiple cell types and surrounded by a proteinaceous extracellular matrix (ECM). Mammary epithelial cells (MECs) represent the fundamental functional unit of the gland and comprise a polariz...

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“…19 However, transient nuclear ESE-1 expression in MCF-10A/MCF-12A benign, non-transformed mammary epithelial cells results in apoptosis 19 and/or decreased cell proliferation, 50 whereas similar nuclear ESE-1 expression in fully transformed mammary epithelial cells fails to induce apoptosis. 19 Although it was previously presumed that many ETS factors transform mammary epithelial cells via their nuclear transcriptional functions, it has been shown that ESE-1 protein is localized within the cytoplasm in human breast cancer cells and that initiation of transformation of benign MCF-12A cells by stable expression of ESE-1 is mediated by the SAR domain of ESE-1, which acts in the cytoplasm via an unknown nonnuclear and non-transcriptional mechanism. 19 Importantly, the nuclear localization of ESE-1 protein maintains the transformed phenotype of fully transformed mammary epithelial cells.…”

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

confidence: 99%

“…19 Although it was previously presumed that many ETS factors transform mammary epithelial cells via their nuclear transcriptional functions, it has been shown that ESE-1 protein is localized within the cytoplasm in human breast cancer cells and that initiation of transformation of benign MCF-12A cells by stable expression of ESE-1 is mediated by the SAR domain of ESE-1, which acts in the cytoplasm via an unknown nonnuclear and non-transcriptional mechanism. 19 Importantly, the nuclear localization of ESE-1 protein maintains the transformed phenotype of fully transformed mammary epithelial cells. 51 Others have reported that the signaling kinase, Pak1, interacts with and selectively phosphorylates ESE-1 at serine 207, which is located within the SAR domain.…”

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

confidence: 99%

“…16 While the A/T hook domain has been shown to mediate binding to the minor groove of AT-rich tracts of double-stranded DNA, 17 the PEST domain is believed to play a role in protein stability owing to protease targeting. 16 Interestingly, ESE-1 also contains a serine-and aspartic acid-rich (SAR) domain, 19 in which a p21-activated kinase-1 (Pak1) phosphorylation site is present. 20 Other members of the ESE subfamily of ETS factors also include ESE-2 (also known as Elf5), ESE-3 (also known as Ehf), and prostate-derived ETS transcription factor (PDEF).…”

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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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The ETS Transcription Factor ESE-1 Transforms MCF-12A Human Mammary Epithelial Cells via a Novel Cytoplasmic Mechanism

Cited by 58 publications

References 48 publications

Profile of Ets gene expression in human breast carcinoma

Profile of Ets gene expression in human breast carcinoma

Use of Three-Dimensional Basement Membrane Cultures to Model Oncogene-Induced Changes in Mammary Epithelial Morphogenesis

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

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