Nucleolin-binding by ErbB2 enhances tumorigenicity of ErbB2-positive breast cancer

Wolfson, Eya; Goldenberg, Maria; Solomon, Shira; Frishberg, Amit; Pinkas‐Kramarski, Ronit

doi:10.18632/oncotarget.11323

Cited by 32 publications

(31 citation statements)

References 35 publications

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“…The results of the present study demonstrate that the association between P-nucleolin expression and survival status is different from that between P-nucleolin expression and overall survival. Previous studies have demonstrated that nucleolin regulates a number of cancer-associated factors and directly or indirectly participates in tumorigenic pathways (28,29). Therefore, the role of P-nucleolin in cancer should be comprehensively evaluated.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Huang

Tan

et al. 2018

Oncol Rep

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Non-small cell lung cancer (NSCLC) is one of the mostly deadly malignancies in the world. Nucleolin is a multifunctional protein that mainly regulates ribosome biogenesis but also has other functions including modulating the transcription of mRNAs and repressing RNA polymerase II. Nucleolin is overexpressed in various cancer cells, including NSCLC cells. It can confer resistance to apoptosis and promote cell migration and blood vessel formation by directly taking part in various tumor signal transduction pathways. The activities of nucleolin are regulated mainly by intracellular localization and post-translational modifications, including phosphorylation, glycosylation, methylation, and ADP-ribosylation. Phosphorylation of nucleolin (P-nucleolin) in NSCLC cells is still not well characterized. In the present study, the levels of nucleolin and P-nucleolin were examined in lung tissue and cells and it was demonstrated that levels of the two forms of nucleolin were significantly increased in NSCLC compared with non-cancerous tissues and cells. In addition, it was demonstrated that high expression levels of nucleolin and P-nucleolin were significantly associated with poor overall survival of NSCLC patients. Doxorubicin (DOX) is a type of anthracycline that has been used in the treatment of various types of cancer, including NSCLC. Upregulation of nucleolin through exogenous expression of nucleolin promoted A549 cell proliferation and migration, while downregulation of nucleolin through expression of small interfering RNA-nucleolin attenuated A549 cell proliferation and migration. Following stimulation with DOX, A549 cell proliferation and migration decreased and the expression of P-nucleolin also decreased. In order to investigate whether P-nucleolin is indispensable to the proliferation and migration of NSCLC cells, a plasmid encoding mutant nucleolin, in which the phosphorylation site at threonine-76 was mutated to alanine, was constructed. Compared with the A549 cells transfected with wild-type nucleolin, P-nucleolin expression and cell proliferation and migration were significantly decreased in A549 cells transfected with mutant nucleolin. These results indicate that targeting P-nucleolin may be a promising strategy for treating NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Huang

Tan

et al. 2018

Oncol Rep

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“…Up to now and as far as we know, only one study reported an association between NCL expression and overall survival in breast cancer. Using the TCGA dataset, Wolfson and colleagues showed that patients carrying HER2-amplified tumours with high NCL expression levels had shorter overall and disease-free survivals than the ones carrying HER2-amplified tumours with low NCL expression levels [ 14 ]. In our hand, no association was observed in HER2-amplified breast cancers in Dundee series.…”

Section: Discussionmentioning

confidence: 99%

“…In breast cancer, only two studies investigated NCL expression. It has been reported that NCL is often overexpressed in breast tumours compared to normal tissues and that NCL overexpression is associated with poor overall survival in HER2-amplified breast cancer [ 14 , 15 ]. Additional studies are required to evaluate more extensively the clinical value of NCL expression in order to understand the role of NCL in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Druggable Nucleolin Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes

Long

Lardy-Cléaud

Bray

et al. 2018

Cancers

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Background: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of NCL and whether NCL stratified cancer patients. Here, we have investigated for the first time the association of NCL with clinical characteristics in breast cancers independently of the different subtypes. Methods: Using two independent series (n = 216; n = 661), we evaluated the prognostic value of NCL in non-metastatic breast cancers using univariate and/or multivariate Cox-regression analyses. Results: We reported that NCL mRNA expression levels are markers of poor survivals independently of tumour size and lymph node invasion status (n = 216). In addition, an association of NCL expression levels with poor survival was observed in TNBC (n = 40, overall survival (OS) p = 0.0287, disease-free survival (DFS) p = 0.0194). Transcriptomic analyses issued from The Cancer Genome Atlas (TCGA) database (n = 661) revealed that breast tumours expressing either low or high NCL mRNA expression levels exhibit different gene expression profiles. These data suggest that tumours expressing high NCL mRNA levels are different from those expressing low NCL mRNA levels. Conclusions: NCL is an independent marker of prognosis in breast cancers. We anticipated that anti-NCL is a promising therapeutic strategy that could rapidly be evaluated in high NCL-expressing tumours to improve breast cancer management.

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“…Moreover, by analyzing data from breast cancer patients, obtained from the Cancer Genome Atlas (TCGA) network, we have found that patients who present with both nucleolin- and ErbB2-positive tumors are at greater disease risk and exhibit lower survival rates compared to ErbB2-positive patients. Importantly, we have found that treatment with the anti-nucleolin G-rich oligonucleotide GroA (AS1411) significantly inhibited the viability and growth of ErbB2-positive breast cancer cells in vitro 20 . Nonetheless, the full scope of GroA treatment in breast cancer, alone and in combination with ErbB2 inhibition, is yet to be examined.…”

Section: Introductionmentioning

confidence: 97%

“…Recently, we have reported that the physical interaction between nucleolin and ErbB2 triggers activation of the receptor and its downstream MAPK signaling 20 . These are accompanied by increased colony formation and anchorage-independent growth of cells overexpressing both proteins.…”

Section: Introductionmentioning

confidence: 99%

Nucleolin and ErbB2 inhibition reduces tumorigenicity of ErbB2-positive breast cancer

et al. 2018

Self Cite

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ErbB2, a member of the ErbB family of receptor tyrosine kinases, is an essential player in the cell’s growth and proliferation signaling pathways. Amplification or overexpression of ErbB2 is observed in ∼30% of breast cancer patients, and often drives cellular transformation and cancer development. Recently, we have shown that ErbB2 interacts with the nuclear-cytoplasmic shuttling protein nucleolin, an interaction which enhances cell transformation in vitro, and increases mortality risk and disease progression rate in human breast cancer patients. Given these results, and since acquired resistance to anti-ErbB2-targeted therapy is a major obstacle in treatment of breast cancer, we have examined the therapeutic potential of targeting the ErbB2–nucleolin complex. The effect of the nucleolin-specific inhibitor GroA (AS1411) on ErbB2-positive breast cancer was tested in vivo, in a mouse xenograft model for breast cancer; as well as in vitro, alone and in combination with the ErbB2 kinase-inhibitor tyrphostin AG-825. Here, we show that in vivo treatment of ErbB2-positive breast tumor xenografts with GroA reduces tumor size and leads to decreased ErbB2-mediated signaling. Moreover, we found that co-treatment of breast cancer cell lines with GroA and the ErbB2 kinase-inhibitor tyrphostin AG-825 enhances the anti-cancer effects exerted by GroA alone in terms of cell viability, mortality, migration, and invasiveness. We, therefore, suggest a novel therapeutic approach, consisting of combined inhibition of ErbB2 and nucleolin, which has the potential to improve breast cancer treatment efficacy.

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Nucleolin-binding by ErbB2 enhances tumorigenicity of ErbB2-positive breast cancer

Cited by 32 publications

References 35 publications

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Druggable Nucleolin Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes

Nucleolin and ErbB2 inhibition reduces tumorigenicity of ErbB2-positive breast cancer

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