Gene copy numbers of HER family in breast cancer

Żaczek, Anna; Wełnicka-Jaśkiewicz, Marzena; Bielawski, Krzysztof Piotr; Jaśkiewicz, Janusz; Badzio, A.; Olszewski, Włodzimierz; Rhone, Piotr; Jassem, Jacek

doi:10.1007/s00432-007-0284-z

Cited by 24 publications

(18 citation statements)

References 36 publications

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“…Amplification of the erbB3 gene has been reported, but PCR and FISH results suggest that this is not as prevalent as erbB2 amplification (34,35) and does not account for the frequency of elevated ErbB3 protein observed in tumors (17). Tumors from transgenic mice overexpressing ErbB2 in the mammary gland exhibit elevated and tyrosine-phosphorylated endogenous ErbB3 (24), pointing to a selective advantage for the co-expression and activation of this receptor in ErbB2-overexpressing tumors.…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional Mechanisms Contribute to the Suppression of the ErbB3 Negative Regulator Protein Nrdp1 in Mammary Tumors

Ingalla

Miller

Wald

et al. 2010

Journal of Biological Chemistry

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The ErbB2 and ErbB3 receptor tyrosine kinases act synergistically to promote cellular properties associated with tumor development. Previous studies indicate that endogenous ErbB3 protein is markedly elevated in mouse mammary tumors induced by transgenic ErbB2 overexpression. However, this occurs in the absence of elevated ErbB3 transcript, indicating that post-transcriptional regulatory mechanisms play crucial roles in suppressing ErbB3 protein in normal tissue. Our previous studies also demonstrate that protein levels of Nrdp1, an E3 ubiquitin ligase that targets ErbB3 for degradation, are markedly suppressed in tumors from ErbB2 transgenic animals relative to normal tissue. Here we demonstrate that transgenic expression of Nrdp1 cDNA in the mouse mammary gland is not sufficient to suppress elevated ErbB3 levels or tumor initiation and growth in ErbB2 transgenic mice. Unexpectedly, Nrdp1 protein is absent in tumors from Nrdp1/ErbB2 bigenic mice, and real time PCR analysis indicates that Nrdp1 protein levels are suppressed post-transcriptionally. Nrdp1 protein is more resistant to proteasome-dependent degradation when exogenously expressed in cultured MCF10A nontransformed human breast epithelial cells than in breast tumor cells. These observations indicate that mammary tumors use potent post-transcriptional mechanisms to suppress Nrdp1 protein levels and that protein destabilization may play a central role in Nrdp1 loss in tumors.Overexpression and aberrant activation of members of the ErbB family of receptor tyrosine kinases are thought to contribute to the development and progression of a variety of tumor types (1). Notably, amplification of the erbB2 gene is observed in 25-30% of breast cancer patients, and overexpression of the ErbB2 protein correlates with earlier relapse and poor prognosis (2, 3). Numerous studies with cultured cells suggest that overexpression of the ErbB2 protein is sufficient to activate its protein-tyrosine kinase activity, which is necessary for ErbB2-induced cellular transformation. ErbB2 overexpression in the mouse mammary gland is sufficient to induce the formation of metastatic tumors (4), underscoring the functional importance of ErbB2 in tumor development. These observations have pointed to a central role for ErbB2 in breast tumor initiation and progression, and ErbB2-directed antibody and small molecule inhibitors are currently employed clinically in the treatment of breast cancer (5, 6).Members of the ErbB family take part in a complex array of combinatorial interactions through the formation homoand heterodimers between the different family members, which in turn activate distinct signaling pathways (7-10). It has been suggested that signaling by the ErbB2-ErbB3 heterodimer is the most potent of the 10 ErbB receptor dimeric complexes (11), and the ErbB2-ErbB3 complex is a proposed oncogenic unit (12). Recent evidence supports a central role for ErbB3 in ErbB2-amplified breast cancer (13), and several reports point to roles for ErbB3 activation in mediating resistance to can...

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Section: Discussionmentioning

confidence: 99%

Post-transcriptional Mechanisms Contribute to the Suppression of the ErbB3 Negative Regulator Protein Nrdp1 in Mammary Tumors

Ingalla

Miller

Wald

et al. 2010

Journal of Biological Chemistry

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“…Most notably, numerous publications have found a strong correlation between erbB2 gene amplification and ErbB2 protein overexpression, and it is generally accepted that elevated gene dosage in tumors is sufficient to drive ErbB2 overexpression. However, ErbB2 protein overexpression is observed in the absence of gene amplification (11,12), and amplification of the erbB3 gene in tumors is rare despite the relative frequency of protein overexpression (64,65). These observations indicate that other mechanisms may also contribute to ErbB aberrantly high protein accumulation in cells.…”

Section: Post-transcriptional Regulation Of Erbb Receptor Levelsmentioning

confidence: 99%

E3 ubiquitin ligases in ErbB receptor quantity control

Carraway

2010

Seminars in Cell & Developmental Biology

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Signaling through ErbB family growth factor receptor tyrosine kinases is necessary for the development and homeostasis of a wide variety of tissue types. However, the intensity of receptormediated cellular signaling must fall within a precise range; insufficient signaling can lead to developmental abnormalities or tissue atrophy, while over-signaling can lead to hyperplastic and ultimately neoplastic events. While a plethora of mechanisms have been described that regulate downstream signaling events, it appears that cells also utilize various mechanisms to regulate their ErbB receptor levels. Such mechanisms are collectively termed "ErbB receptor quantity control." Notably, studies over the past few years have highlighted roles for post-transcriptional processes, particularly protein degradation, in ErbB quantity control. Here the involvement of ErbB-directed E3 ubiquitin ligases is discussed, including Nrdp1-mediated ErbB3 degradation, ErbB4 degradation mediated by Nedd4 family E3 ligases, and CHIP-mediated ErbB2 degradation. The hypothesis is forwarded that protein degradation-based ErbB quantity control mechanisms play central roles in suppressing receptor overexpression in normal cells, and that the loss of such mechanisms could facilitate the onset or progression of ErbB-dependent tumors.

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“…Previous reports indicated the importance of the interaction of ERBB2 with other ERBB receptors (ERBB1 ERBB3, ERBB4). This interaction may be associated with a more aggressive phenotype (19,20). PI3K and MYC are downstream effectors of ERBB receptors.…”

Section: Introductionmentioning

confidence: 99%

A multimarker qPCR platform for the characterisation of endometrial cancer

et al. 2013

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Abstract. The molecular background of endometrial cancer (EC) has not been fully elucidated. In the present study, we developed a quantitative PCR (qPCR) platform to examine the gene dosages of the potential molecular markers MGB1, TOP2A, ERBB1-4, MYC, CCND1, ESR1 and PI3K. The platform was applied in samples collected from 157 EC patients (stage I-IV) to verify its clinical utility and to examine the diagnostic and prognostic significance of the analysed biomarkers. The gene dosage pattern of the ERBB family and its downstream effectors PI3K and MYC showed particularly strong correlations with clinicopathological data. The ERBB PI3K/Akt pathway was upregulated in 31 (20%) of 156 cases. Activation of the ERBB PI3K/Akt pathway was positively correlated with a higher stage (p=0.001), higher grade (p=0.001), histological type II disease (p=0.0003) and metastases (p=0.02). The implemented hierarchical clustering revealed that cluster 2 was characterised by high copy numbers of the studied genes. Cluster 2 was associated with shorter overall survival (p=0.05). The platform was found to be a fast and simple method for direct analysis of the genes involved in uterine carcinogenesis, making it feasible for EC biology characterisation.

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Gene copy numbers of HER family in breast cancer

Cited by 24 publications

References 36 publications

Post-transcriptional Mechanisms Contribute to the Suppression of the ErbB3 Negative Regulator Protein Nrdp1 in Mammary Tumors

Post-transcriptional Mechanisms Contribute to the Suppression of the ErbB3 Negative Regulator Protein Nrdp1 in Mammary Tumors

E3 ubiquitin ligases in ErbB receptor quantity control

A multimarker qPCR platform for the characterisation of endometrial cancer

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