Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients

Sassen, A.; Rochon, Justine; Wild, Peter J.; Hartmann, Arndt; Hofstaedter, Ferdinand; Schwarz, Stephan; Brockhoff, Gero

doi:10.1186/bcr1843

Cited by 129 publications

(135 citation statements)

References 54 publications

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“…In addition, we demonstrated a positive association between HER2 and HER3 mRNA expression. A similar correlation was described earlier, both at the mRNA and protein level (Bieche et al, 2003;Witton et al, 2003;Sassen et al, 2008). It has been suggested that the HER2/HER3 heterodimer constitutes the most mitogenic dimer in the HER family (Citri et al, 2003).…”

Section: Discussionsupporting

confidence: 65%

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Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

et al. 2008

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The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT -PCR). The overall concordance between kRT -PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT -PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas.

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Section: Discussionsupporting

confidence: 65%

“…A number of studies evaluating HER family receptors have indicated a negative prognostic value of HER3 in breast cancer patients (Bieche et al, 2003;Witton et al, 2003;Sassen et al, 2008). In contrast, our present study showed a positive association between HER3 mRNA expression and OS.…”

Section: Discussioncontrasting

confidence: 56%

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

et al. 2008

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“…The role of Her4 in breast cancer development has been considered ambiguous, partly because of a lack of mechanistic knowledge about its mode of action (21, [31][32][33][34][35]. In this context, our study sheds light on the mechanism of action of Her4 by showing that its active form is required to stabilize the MDMX-MDM2 complex, as we demonstrated using a ␥-secretase inhibitor to prevent Her4 activation in response to NRG1 stimulation.…”

Section: Discussionmentioning

confidence: 91%

“…Her4 signal (35). With the search criteria based on high stringency, the software identified two candidate kinases, CDK4/6 and p38 (Fig.…”

Section: Cdk4/6 Mediates Her4 Stabilization Of Mdmx-mdm2 and Its Suppmentioning

confidence: 99%

Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex

Gerarduzzi¹,

Polo²,

Liu³

et al. 2016

Journal of Biological Chemistry

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Edited by Eric FearonDeregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes. Using a phospho-proteomics approach, we functionally identified a novel Her4-induced posttranslational modification on MDMX at Ser-314, a putative phosphorylation site for the CDK4/6 kinase. Remarkably, inhibition of Ser-314 phosphorylation either with Ser-to-Ala substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX-MDM2 and rescued p53 activity. Our study offers insights into the mechanisms of deregulated RTK-induced carcinogenesis and provides the basis for the use of inhibitors targeting RTKmediated signals for p53 restoration. p53 is either mutated or functionally inactive in most human cancers. Several tumor types that retain wild-type p53 (i.e. breast cancer) display higher protein levels of MDMX and/or MDM2 2 (1-8), the primary inhibitors of p53, representing alternative mechanisms of p53 inactivation. Typically, p53 protein levels are tightly controlled and modulated by its principle negative regulator, the MDMX-MDM2 complex. Given that MDMX and MDM2 are amplified in many tumors, modulation of their stability offers an attractive therapeutic strategy to restore p53 function and so improve tumor responsiveness to DNA-damaging therapy.Although MDM2 is the main negative regulator of p53, there is now growing evidence supporting the notion that MDMX also plays a key role in modulating p53, mainly through its stabilization of MDM2 (9). In fact, the MDMX-MDM2 heterocomplex is the main form in which the two proteins are found in the cell (10, 11), and loss of this formation leads to p53 activation and embryonic lethality (9, 11-13).Under non-stressed conditions, MDMX and MDM2 suppress p53 activity. However, under stress conditions, MDMX and MDM2 are posttranslationally modified and disabled for their inhibition of p53. As a result, p53 can then respond to the stress and repair any damage. MDM2 and MDMX are structural homologs, with the major distinction that MDM2 contains an E3 ligase domain, a nuclear localization signal domain, and a nuclear export signal domain (14). There are two major ways in which p53 activity can be suppressed by the complex. First, MDM2 and MDMX can cooperatively bind to the transactivational domain of p53 and suppress its transcriptional activity. Second, MDM2 can act as an E3 ligase and induce p53 ubiquitination an...

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“…85 Several studies have demonstrated that HER3 is frequently co-expressed with HER2 in breast cancer, and HER3 has a role in HER2-mediated breast carcinogenesis. 86,87 Iorio et al 81 suggested that the reintroduction of miR-205 into SKBr3 cell increases the responsiveness of lapatinib (tyrosine kinase inhibitors) avoiding HER3-mediated resistance and restoring potent proapoptotic activity. Wang et al 88 predicted that miR-205 binds to the 3′ untranslated regions of HER3 mRNA, and the upregulation of miR-205 reduced HER3 protein expression.…”

Section: Mirna In Hormone Receptor-positive/her2-negative Breast Cancermentioning

confidence: 99%

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

et al. 2016

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MicroRNAs (miRNAs) are short non-coding RNAs that regulate the function of target genes at the post-transcriptional phase. miRNAs are considered to have roles in the development, progression and metastasis of cancer. Recent studies have indicated that particular miRNA signatures are correlated with tumor aggressiveness, response to drug therapy and patient outcome in breast cancer. On the other hand, in routine clinical practice, the treatment regimens for breast cancer are determined based on the intrinsic subtype of the primary tumor. Previous studies have shown that miRNA expression profiles of each intrinsic subtypes of breast cancer differ. In hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, miRNA expressions are found to be correlated with endocrine therapy resistance, progesterone receptor expression and heat shock protein activity. Some miRNAs are associated with resistance to HER2-targeted therapy and HER3 expression in HER2-positive breast cancer. In triple-negative breast cancer, miRNA expressions are found to be associated with BRCA mutations, immune system, epithelial-mesenchymal transition, cancer stem cell properties and androgen receptor expression. As it has been clarified that the expression levels and functions of miRNA differ among the various subtypes of breast cancer, and it is necessary to take account of the characteristics of each breast cancer subtype during research into the roles of miRNA in breast cancer. In addition, the discovery of the roles played by miRNAs in breast cancer might provide new opportunities for the development of novel strategies for diagnosing and treating breast cancer.

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Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients

Cited by 129 publications

References 54 publications

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) study

Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

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