A positive role for PEA3 in HER2-mediated breast tumour progression (original) (raw)
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Expression of PEA3 and Lack of Correlation Between PEA3 and HER-2/neu Expression in Breast Cancer
Breast Cancer Research and Treatment, 2006
The ETS protein PEA3 functions as a transcription factor to regulate gene expression. Although members of the ETS family have been reported to be involved in tumor progression, ectopic expression of PEA3 has been shown to suppress tumor formation. Despite several studies demonstrated frequent expression of PEA3 and its high association with HER-2/neu and have suggested a potential role of PEA3 in breast cancer, contradictory result has shown that the PEA3 was associated with better survival rate in breast cancer. In the current study, we address this discrepancy by examining the expression of PEA3 and HER-2/neu on 289 archived breast cancer tumor tissues and their correlation with clinicopathologic factors and prognosis. The staining of PEA3 was further validated by in situ hybridization for PEA3 mRNA. We found PEA3 was positive in 22.2% (64/289) of all cases and only 25.6% (21/82) of HER-2/neu-overexpressing cases showed co-expression of PEA3. In contrast to HER-2/neu, PEA3 expression was not correlated with prognosis or major clinicopathologic factors, except for a negative correlation with lymphovascular permeation ( p=0.007). This study demonstrates that PEA3 expression is not correlated with HER-2/ neu expression in breast cancer tumor tissues, nor is it associated with adverse clinicopathologic factors or prognosis.
The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase
Oncogene, 1998
The HER2/neu gene, which is overexpressed in 20 ± 30% of human breast tumors, encodes a receptor tyrosine kinase that functions through multiple signaling pathways to regulate the activity of nuclear transcription factors. We have reported that PEA3, an Ets family transcription factor, is overexpressed in HER2/Neuinduced breast tumors and their metastases. To account for the increased levels of PEA3 in these tumors we have suggested that HER2/Neu enhances PEA3 transcriptional activity, which then acts to stimulate expression of the PEA3 gene. This hypothesis is consistent with the occurrence of PEA3 binding sites in the PEA3 promoter and with the ability of PEA3 to transactivate this promoter. To learn whether HER2/Neu indeed regulates PEA3 activity we measured the capacity of constitutively-activated HER2/Neu to aect PEA3-dependent reporter gene expression. Coexpression of PEA3 and HER2/Neu stimulated PEA3-dependent reporter gene expression to a much greater extent than did either protein alone suggesting that HER2/Neu upregulates the transcriptional activity of PEA3. To de®ne the pathway whereby HER2/Neu functions we employed dominantnegative mutants of signaling proteins known to be downstream of HER2/Neu. Overexpression of Rap1a, a Ras-related protein capable of antagonizing Ras function, completely inhibited the ability of HER2/Neu to stimulate PEA3-dependent gene expression. Ras is known to stimulate at least two mitogen-activated protein kinase (MAPK) cascades, the extracellularregulated kinase (ERK) cascade and the stress-activated kinase (SAPK) or Jun kinase (JNK) cascade. Similarly, HER2/Neu activated both ERKs and SAPKs/JNKs in a Ras-dependent fashion. Dominant-inhibitory mutants in either the ERK or SAPK/JNK cascades partially inhibited HER2/Neu activation of PEA3-dependent gene expression. These ®ndings suggest that HER2/Neu regulates PEA3 activity through two dierent Rasdependent MAPK pathways.
Journal of data mining in genomics & proteomics, 2012
Amplification and expression of the HER2/ErbB2 oncogene in breast cancer occurs in 25-40% of cases and is associated with aggressive disease [1-4]. HER2/ErbB2 is a transmembrane tyrosine kinase of the EGF (Epidermal Growth Factor) receptor family. The receptor readily dimerizes leading to autophosphorylation and activation of heterodimer partners [5-6]. These partners include EGFR/ErbB1/HER1, HER4 and especially HER3 [5-7]. The activated receptors in turn recruit adaptor proteins which sequester substrates for downstream activation. HER2 signals through at least four major pathways including the Map kinase, PI3K/Akt, Phospholipase C, and STAT pathways [8-11]. The Map kinase pathway leads to the activation of genes that promote cell proliferation. PI3K/Akt promotes down regulation of several intermediates of apoptosis thereby promoting increased cell survival. Together these effects provide a potential mechanism for the oncogenic role of HER2. An important landmark in breast cancer therapy was the development of the humanized monoclonal antibody, Herceptin/Trastuzumab, directed against the extracellular portion of HER2. However, in spite of advances in targeted therapy and good responses with combined anti-HER2+/chemotherapy approaches, diverse mechanisms of resistance to treatment are apparent in breast cancers with amplified HER2 [12] and recurrence is common. A durable therapy has been elusive. Detailed expression analysis studies have provided lists of potential genes whose transcript levels are influenced by HER2 [13]. This information is vital for understanding resistance, for devising new treatments, and for understanding how the aggressive properties of HER2+ breast cancer are achieved. We studied MCF7 breast cancer cells that either expressed large amounts of active HER2 or did not express HER2, as well as breast cancer cell lines with naturally amplified HER2; BT474 and MDA453. We performed whole genome expression analysis using U133 plus 2 arrays with ~54,000 probe sets. We compared these data to the distribution of RNA Polymerase II (POL II) bound to promoters and the adjacent exons. This data was obtained using chromatin immunoprecipitation (ChIP) with antibodies to POL
Carcinogenesis, 2003
The PEA3/E1AF/ETV4 gene encodes an Ets-related transcription factor that is expressed in the epithelial cells of the mammary gland. Previous reports have shown that PEA3 can up-regulate promoter activities of many genes associated with tumorigenesis. A significant fraction of those encode matrix metalloproteinases (MMP genes) required for degradation of the extracellular matrix. To better obtain a molecular characterization of PEA3 expression in sporadic breast cancer, we quantified PEA3 mRNA by means of real-time reverse transcriptase±polymerase chain reaction assay in a large series of human primary breast tumors. PEA3 expression showed wide variations in tumor tissues, being under-expressed in 30 of 130 (23.1%) and over-expressed in 18 of 130 (13.8%) compared with normal breast tissues. High PEA3 mRNA levels correlated significantly with Scarff±Bloom±Richardson histopathological grade III (P 0.018) but not with poor prognosis, suggesting that PEA3 is a marker of tumor aggressiveness rather than a prognostic factor in human breast cancer. We also observed positive links between the expression of PEA3 and those of MKI67 and ERBB2 (P 0.034 and P 0.045, respectively) and an inverse relationship with ERa (P 0.0016). Our results do not support recent findings suggesting that PEA3 could be a tumor-suppressor gene that can act therapeutically in ERBB2 over-expressed tumors. Our results also suggest major roles of the MMP2, NRG1 and CGB genes (which encode type I gelatinase, heregulin and human chorionic gonadotropin b subunit, respectively) in the PEA3 pathway dysregulation observed in breast cancer. Taken together, the data confirm the role of the PEA3 gene in breast tumorigenesis, and suggest the existence of numerous other still unknown genes transactivated by the PEA3 transcription factor.
Journal of Clinical Pathology, 2004
Background: In human breast cancer, the growth factor receptor HER2 is associated with disease progression and resistance to endocrine treatment. Growth factor induced mitogen activated protein kinase activity can phosphorylate not only the oestrogen receptor, but also its coactivator proteins AIB1 and SRC-1. Aim: To determine whether insensitivity to endocrine treatment in HER2 positive patients is associated with enhanced expression of coactivator proteins, expression of the HER2 transcriptional regulator, PEA3, and coregulatory proteins, AIB1 and SRC-1, was assessed in a cohort of patients with breast cancer of known HER2 status. Methods: PEA3, AIB1, and SRC-1 protein expression in 70 primary breast tumours of known HER2 status (HER2 positive, n = 35) and six reduction mammoplasties was assessed using immunohistochemistry. Colocalisation of PEA3 with AIB1 and SRC-1 was determined using immunofluorescence. Expression of PEA3, AIB1, and SRC-1 was correlated with clinicopathological parameters. Results: In primary breast tumours expression of PEA3, AIB1, and SRC-1 was associated with HER2 status (p = 0.0486, p = 0.0444, and p = 0.0012, respectively). In the HER2 positive population, PEA3 expression was associated with SRC-1 (p = 0.0354), and both PEA3 and SRC-1 were significantly associated with recurrence on univariate analysis (p = 0.0345; p,0.0001). On multivariate analysis, SRC-1 was significantly associated with disease recurrence in HER2 positive patients (p = 0.0066). Conclusion: Patients with high expression of HER2 in combination with SRC-1 have a greater probability of recurrence on endocrine treatment compared with those who are HER2 positive but SRC-1 negative. SRC-1 may be an important predictive indicator and therapeutic target in breast cancer.
Cancer Research, 2007
In some HER2-positive breast tumors, cell surface overexpression of HER2 is not associated with gene amplification but may instead rest in altered gene transcription, half-life, or recycling of the oncoprotein. Here, we show that HER2 overexpression in HER2 2+ carcinomas is associated with neither an increase in gene transcription nor a deregulation in the ubiquitin-dependent pathways, but instead seems to be regulated by protein kinase CA (PKCA) activity. The stimulation of PKCA up-regulated HER2 expression, whereas PKCA inhibition by pharmacologic treatments and PKCA-specific small interfering RNA led to a dramatic down-regulation of HER2 levels only in breast cancer cells HER2 2+. Consistent with the in vitro data, our biochemical analysis of HER2 2+ human primary breast specimens revealed significantly higher levels of phosphorylated PKCA compared with HER2-negative tumors. Inhibition of HER2 activation by the tyrosine kinase inhibitor lapatinib led to decreased levels of PKCA phosphorylation, clearly indicating a cross-talk between PKCA and HER2 molecules. These data suggest that HER2 overexpression in HER2 2+ carcinomas is due to an accumulation of the recycled oncoprotein to the cell surface induced by activated PKCA. [Cancer Res 2007;67(11):5308-17]