Expression of PEA3 and Lack of Correlation Between PEA3 and HER-2/neu Expression in Breast Cancer

Xia, Wei; Lien, Han‐Chung; Wang, Shao‐Chun; Pan, Yii‐Wen; Şahin, Ayşegül; Kuo, Yau Hung; Chang, King‐Jen; Zhou, Xin; Wang, Hongying; Yu, Zhengming; Hortobágyi, Gabriel N.; Shi, Dar Ren; Hung, Mien Chie

doi:10.1007/s10549-006-9162-7

Cited by 16 publications

(14 citation statements)

References 32 publications

(34 reference statements)

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“…Another study found PEA3 protein expression in 22.2% (64/289) of breast cancers, but failed to find correlation with HER2/neu expression [83].…”

Section: Pea3mentioning

confidence: 94%

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

Watson¹,

Turner²,

Scheiber³

et al. 2010

TOCJ

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ETS factors are known to act as positive or negative regulators of the expression of genes including those that control response to various signaling cascades, cellular proliferation, differentiation, hematopoiesis, apoptosis, adhesion, migration, invasion and metastasis, tissue remodeling, ECM composition and angiogenesis. During cancer progression, altered ETS gene expression disrupts the regulated control of many of these biological processes. Although it was originally observed that specific ETS factors function either as positive or negative regulators of transcription, it is now evident that the same ETS factor may function in reciprocal fashions, reflecting promoter and cell context specificities. This report will present a discussion of ETS factor expression during prostate and breast cancer progression and its functional roles in epithelial cell phenotypes.The ETS genes encode transcription factors that have independent activities but are likely to be part of an integrated network. While previous studies have focused on single ETS factors in the context of specific promoters, future studies should consider the functional impact of multiple ETS present within a specific cell type. The pattern of ETS expression within a single tissue is, not surprisingly, quite complex. Multiple ETS factors may be able to regulate the same genes, albeit at different magnitude or in different directions. Furthermore, the precise balance between cancer promotion and inhibition by ETS factors, which may differentially regulate specific target genes, can thus control its progression. These concepts form the basis of the hypothesis that "Ets conversion" plays a critical role during tumor progression. Examples supporting this hypothesis will be described.Keywords: ETS, transcription, prostate cancer, breast cancer, cancer progression, biological control. ETS GENE FAMILYThe oncogene v-ets was first characterized in 1983 as part of the transforming fusion protein of an avian retrovirus, E26 (ets, E26 transforming sequence). Subsequent identification of v-ets related genes from metazoan species established the Ets family as one of the largest families of transcriptional regulators, with diverse functions and activities (for reviews, see [1][2][3][4] and references therein). To date, 27 human ETS family members have been identified (Fig. (1) and Table 1). All Ets genes retain a conserved winged helixturn-helix DNA binding domain (the ETS domain) of ~ 85 amino acids that recognizes a core GGAA/T sequence (ETS binding site, EBS). ETS proteins, with the exception of GABPα, bind DNA as monomers. The second conserved domain found in a subset of ETS genes is the pointed (PNT) domain. This 65-85 amino acid domain is found in 11 of 27 human ETS genes and has been shown to function in protein-protein interaction and oligomerization. ETS factors have been classified into 12 subgroups based upon Ets domain sequence homology: ETS, ERG, PEA3, ETV2, TCF, GABP, ELF, SPI, TEL, ERF, PDEF and ESE [2, 5] (See Table 1 for subgroup members). ...

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“…Another study found PEA3 protein expression in 22.2% (64/289) of breast cancers, but failed to find correlation with HER2/neu expression [83].…”

Section: Pea3mentioning

confidence: 94%

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

Watson¹,

Turner²,

Scheiber³

et al. 2010

TOCJ

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“…HER2 overexpressing breast cancer cells lines, like BT-474, MDA-453, and ZR-751, show a 30-fold enhanced activity of PEA3 for its binding site on the HER2 promoter. Although the majority of evidence supports a model whereby PEA3 and HER2 are locked in a positive feedback loop, there is some controversy, since a few reports suggest an anti-tumor role of PEA3 in breast cancer and that there is no significant correlation of HER2/Neu and PEA3 expression (Xia et al, 2006, Yu et al, 2006). Evidence for a definitive role of PEA3 downstream of HER2 and in oncogenesis comes from studies using dominant-negative proteins to inhibit signaling steps downstream of HER2 (O’Hagan and Hassell, 1998, Shepherd et al, 2001).…”

Section: B Mechanisms Of Ets Protein Mediated Oncogenesismentioning

confidence: 99%

Molecular mechanisms of ETS transcription factor-mediated tumorigenesis

Kar¹,

Gutierrez‐Hartmann

2013

Critical Reviews in Biochemistry and Molecular Biology

117

106

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The ETS family of transcription factors is critical for development, differentiation, proliferation and also has a role in apoptosis and tissue remodeling. Changes in expression of ETS proteins therefore have a significant impact on normal physiology of the cell. Transcriptional consequences of ETS protein deregulation by overexpression, gene fusion, and modulation by RAS/MAPK signaling are linked to alterations in normal cell functions, and lead to unlimited increased proliferation, sustained angiogenesis, invasion and metastasis. Existing data show that ETS proteins control pathways in epithelial cells as well as stromal compartments, and the crosstalk between the two is essential for normal development and cancer. In this review we have focused on ETS factors with a known contribution in cancer development. Instead of focusing on a prototype, we address cancer associated ETS proteins and have highlighted the diverse mechanisms by which they affect carcinogenesis. Finally, we discuss strategies for ETS factor targeting as a potential means for cancer therapeutics.

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“…Real-time polymerase chain reaction (RT-PCR) studies showed that down-regulation of HER2 mRNA levels closely correlated with FASN blockade-induced reduction of HER2 protein expression, thus suggesting that changes in HER2 oncogene expression upon pharmacological inhibition of FASN activity resulted from effects at the transcriptional level (22). Indeed, FASN inhibition was found to up-regulate the expression of the Ets class transcription factor PEA3, a potent trans-repressor of HER2 promoter activity that specifically reverses the in vitro transformed phenotype of HER2-overexpressing cancer cells and inhibits HER2-induced tumorigenesis in vivo (30)(31)(32)(33). When transient transfection experiments with a Luciferase reporter gene driven by the HER2 promoter were performed in HER2-overexpressing breast cancer cells, treatment with chemical FASN blockers such as C75 profoundly repressed the constitutive hyperactivity of the HER2 gene promoter (25)(26)(27)(28).…”

Section: Pharmacological Blockade Of Fatty Acid Synthase (Fasn) Revermentioning

confidence: 99%

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

Vázquez-Martín

Colomer²,

Brunet³

et al. 2007

Int J Oncol

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Abstract. Elucidating the mechanisms underlying resistance to the human epidermal growth factor receptor 2 (HER2)-targeted antibody trastuzumab (Tzb; Herceptin™) is a major challenge that is beginning to be addressed. This dilemma is becoming increasingly important as recent studies strongly support a role for Tzb in the adjuvant setting for HER2-overexpressing early-stage breast cancers. We previously reported that pharmacological and RNA interference-induced inhibition of tumor-associated fatty acid synthase (FASN; Oncogenic antigen-519), a key metabolic enzyme catalyzing the synthesis of long-chain saturated fatty acids, drastically down-regulates HER2 expression in human breast cancer cells bearing HER2 gene amplification. Given that FASN blockade was found to suppress HER2 overexpression by attenuating the promoter activity of the HER2 gene, we here envisioned that this mechanism of action may represent a valuable strategy in breast cancers that have progressed while under Tzb. We created a preclinical model of Tzb resistance by continuously growing HER2-overexpressing SKBR3 breast cancer cells in the presence of clinically relevant concentrations of Tzb (20-185 μg/ml Tzb). This pool of Tzb-conditioned SKBR3 cells, which optimally grows now in the presence of 100 μg/ml trastuzumab (SKBR3/Tzb100 cells), exhibited HER2 levels notably higher (~2-fold) than those found in SKBR3 parental cells. Real-time polymerase chain reaction studies showed that up-regulation of HER2 mRNA levels closely correlated with HER2 protein up-regulation in SKBR3/ Tzb100 cells, thus suggesting that 'HER2 super-expression' upon acquisition of autoresistance to Tzb resulted, at least in part, from up-regulatory effects in the transcriptional rate of the HER2 gene. SKBR3/Tzb100 cells did not exhibit crossresistance to C75, a small-compound specifically inhibiting FASN activity. On the contrary, SKBR3/Tzb100 cells showed a remarkably increased sensitivity (~3-fold) to the cytotoxic effects occurring upon C75-induced inhibition of FASN enzymatic activity. Both HER2 mRNA and HER2 protein 'super-expression', which have not been reported in earlier Tzb-resistant breast cancer models, were entirely suppressed following pharmacological blockade of FASN activity. Moreover, while Tzb was still able to reduce HER2 protein expression by ~20% in SKBR/Tzb100 cells, C75 and Tzb coexposure synergistically down-regulated HER2 protein levels by >85%. The nature of the interaction between Tzb and C75 in Tzb-resistant SKBR3/Tzb100 cells was also found to be strongly synergistic when analyzing the extent of apoptotic cell death using ELISA-based detection of histone-associated DNA fragments. In summary, a) the molecular mechanism(s) contributing to Tzb resistance in our SKBR3/Tzb100 model appear to be clearly different to those previously reported as we found important transcriptional up-regulatory transcriptional changes in HER2 gene expression levels relative to parental cells; b) since FASN inhibition acts on HER2 gene expression via reduction of its tr...

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Expression of PEA3 and Lack of Correlation Between PEA3 and HER-2/neu Expression in Breast Cancer

Cited by 16 publications

References 32 publications

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

ETS Transcription Factor Expression and Conversion During Prostate and Breast Cancer Progression

Molecular mechanisms of ETS transcription factor-mediated tumorigenesis

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

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