HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer

Benz, Christopher C.; O’Hagan, Ronan; Richter, Birgit; Scott, Gary K.; Chang, Chia Hui; Xiong, Xiaoxing; Chew, Karen; Ljung, Britt Marie; Edgerton, Susan M.; Thor, Ann D.; Hassell, John A.

doi:10.1038/sj.onc.1201331

Cited by 148 publications

(132 citation statements)

References 28 publications

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“…34 This observation contrasted with the frequent overexpression of Etv4/Pea3 that is a downstream target of the HER-2/neu receptor tyrosine kinase in breast cancer. 35 These inconsistent findings reflect the complex nature of Ets biology that is highly context-dependent. This is not surprising, however, given that the direction of transcriptional regulation by Ets proteins is markedly affected by upstream stimulation and their interacting cofactors, which are controlled in both temporal and spatial fashion.…”

Section: Discussionmentioning

confidence: 78%

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: 78%

Profile of Ets gene expression in human breast carcinoma

Pan

Hu³

et al. 2007

Cancer Biology & Therapy

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“…Furthermore, ER81, or the related ETS proteins ERM and PEA3, appear to be overexpressed in HER2/Neu-overexpressing human breast cancers, and transgenic mice overexpressing HER2/Neu in mammary tissue accordingly display a coordinate up-regulation of ER81, ERM, and PEA3 (42, 45, 74). Also, both ER81 and PEA3 have been shown to activate HER2/Neu transcription, thereby establishing a positive feedback loop (53,75). Regarding all these facts, HER2/Neu and ER81, or ERM or PEA3, are destined to cooperate in up-regulating Smad7.…”

Section: Smad7 Activation By Her2/neu Tak1 and Er81mentioning

confidence: 99%

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

Dowdy¹,

Mariani²,

Janknecht

2003

Journal of Biological Chemistry

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The cytokine transforming growth factor ␤ (TGF-␤) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-␤ signaling components or enhanced expression of inhibitors of the TGF-␤ pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 upregulation. Moreover, we show that TAK1, a TGF-␤-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-␤ signaling by activating Smad7 transcription may proceed not only through TGF-␤ receptorregulated Smad proteins but also through an independent pathway involving ER81 and TAK1.

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“…76% of all human breast tumors contain elevated levels of PEA3 RNA; 93% of the c-ERB-B2/HER2-positive subclass of these tumors overexpress PEA3 (20). PEA3 is also overexpressed in mouse mammary tumors arising in transgenic mice engineered to express murine c-Erb-B2/Her2 in their mammary glands (19).…”

mentioning

confidence: 99%

“…PEA3 is overexpressed in breast tumors both in humans and mice, suggesting a role for PEA3 in this malignancy (19,20). 76% of all human breast tumors contain elevated levels of PEA3 RNA; 93% of the c-ERB-B2/HER2-positive subclass of these tumors overexpress PEA3 (20).…”

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confidence: 99%

“…The overall amino acid sequence similarity of the PEA3 1 subfamily is ϳ50% (17). The three longest stretches of greatest sequence similarity include the 85-amino acid ETS domain (95% sequence identity); an acidic region near the amino terminus composed of 32 amino acids (85% sequence identity); and a region at the carboxyl terminus comprising ϳ60 amino acids (50% sequence identity) (17).PEA3 is overexpressed in breast tumors both in humans and mice, suggesting a role for PEA3 in this malignancy (19,20). 76% of all human breast tumors contain elevated levels of PEA3 RNA; 93% of the c-ERB-B2/HER2-positive subclass of these tumors overexpress PEA3 (20).…”

mentioning

confidence: 99%

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The PEA3 Ets Transcription Factor Comprises Multiple Domains That Regulate Transactivation and DNA Binding

Bojović

Hassell

2001

Journal of Biological Chemistry

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PEA3, a member of the Ets family of transcription factors, is a nuclear phosphoprotein capable of activating transcription. Mouse PEA3 comprises 480 amino acids and bears an ϳ85-amino acid ETS domain near its carboxyl terminus. Whereas analyses of bacterially expressed PEA3 revealed that the ETS domain is required for sequence-specific DNA binding, little is known of the functional domains in the protein required for its activity in mammalian cells. To this end, we defined the location of the PEA3 functional domains in COS cells. PEA3 bears a strong activation domain near its amino terminus, which is flanked by two regions that independently negatively regulate its activity. PEA3 expressed in COS cells was incapable of binding to DNA in vitro. However, DNA binding activity could be unmasked by incubation with a PEA3-specific antibody. Analyses of the DNA binding activity of PEA3 deletion mutants revealed that two regions flanking the ETS domain independently inhibited DNA binding; deletion of both regions was required to detect DNA binding in the absence of a PEA3-specific antibody. Under these conditions, the ETS domain was sufficient for sequence-specific DNA binding. These findings suggest that the activity of PEA3 is exquisitely controlled at multiple functional levels.The Ets family of transcription factors are defined by an evolutionarily conserved ϳ85-amino ETS domain (1). These proteins are found exclusively in multicellular organisms and are thought to play cardinal roles in development and oncogenesis (2). Multiple ets genes have been identified in individual organisms; over 20 mammalian genes have been discovered thus far (3). Ets proteins are sequence-specific DNA-binding proteins that regulate transcription (reviewed in Ref. 2). Generally, these proteins activate transcription, but several members of the family are known to repress this process. DNA binding is achieved by interaction between the ETS domain and an ϳ10-base pair sequence element termed the Ets binding site comprising a highly conserved central core sequence, 5Ј-GGA(A/T)-3Ј. Individual Ets proteins demonstrate specificity for sequences flanking this core, but it is not uncommon for different Ets proteins to bind to the same Ets binding site. Structural analyses of the ETS domain reveal a winged-helixturn-helix structure akin to that of the Escherichia coli catabolite activator protein and the HNF3/forkhead and heat shock transcription factors (4 -7).Mouse pea3 (8) (the human gene is named ETV4 and has also been termed E1A-F) (9, 10) is the founding member of the pea3 subfamily of ets genes. This subfamily also includes er81 (ETV1) (11-13) and erm (ETV5) (14, 15). Each of these genes is located on a different chromosome (16), but all three genes share a common architecture comprising 14 equivalently sized exons that encode similar sequences of the respective proteins (16 -18). The overall amino acid sequence similarity of the PEA3 1 subfamily is ϳ50% (17). The three longest stretches of greatest sequence similarity include the 85-amino ...

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HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer

Cited by 148 publications

References 28 publications

Profile of Ets gene expression in human breast carcinoma

Profile of Ets gene expression in human breast carcinoma

HER2/Neu- and TAK1-mediated Up-regulation of the Transforming Growth Factor β Inhibitor Smad7 via the ETS Protein ER81

The PEA3 Ets Transcription Factor Comprises Multiple Domains That Regulate Transactivation and DNA Binding

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