IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells

Perks, Claire M; Vernon, Ellen; Rosendahl, AH; Tonge, David W.; Holly, Jeffrey M P

doi:10.1038/sj.onc.1210397

Cited by 99 publications

(105 citation statements)

References 31 publications

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“…Interestingly, prolonged stimulation of schwannoma cells with recombinant IGFBP-1 increases AKT activity ( Figure 6). As PTEN is an important AKT antagonist regulating cell growth (Blanco-Aparicio et al, 2007;Liu et al, 2008;Feron et al, 2009) (Perks et al, 2007), IGFBP-1 also contributes to the downregulation of PTEN (Figure 6). Thus, based on our data we here demonstrate a novel mechanism involved in schwannoma development via autocrine release of IGFBP-1, which downregulates PTEN leading to increased AKT activity and survival of schwannoma cells ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…Normal nerve (Figure 1d, upper right panel) and traumatic neuroma (Figure 1d, middle right panel) expressed IGFBP-1 weakly compared with schwannoma. As IGFBP-2 acts via the same integrins as IGFBP-1 (Perks et al, 2007), displaying some similarities in signalling (Wheatcroft and Kearney, 2009), we tested whether Schwann and schwannoma cells release IGFBP-2. We demonstrated that both cell types release IGFBP-2 equally (Figure 1e).…”

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

“…PTEN is downregulated in schwannoma via IGFBP-1 PTEN is a tumour suppressor downregulated in many cancers (Li et al, 1997) and has been shown to be downregulated by IGFBP-2 acting, similarly to IGFBP-1, via a5/b1-integrins (Perks et al, 2007). We have therefore investigated the expression of PTEN in schwannoma cells compared with Schwann cells and the role of IGFBP-1.…”

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

“…As shown in other cancer models IGFBP-1, through its COOHterminal RGD motif (Jones et al, 1993b;Yee, 2002), can act via b1-integrin toward FAK (Zumkeller and Westphal, 2001;Zhang and Yee, 2006;Perks et al, 2007) both strongly overexpressed and basally activated in schwannoma Ammoun et al, 2008) and may potentiate cell proliferation, migration and survival (Giancotti and Ruoslahti, 1999). Therefore, we wondered what role IGFBP-1 has in schwannoma development.…”

Section: Introductionmentioning

confidence: 97%

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Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via b1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin b1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of antiapoptotic AKT. Thus, IGFBP-1/integrin b1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.

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Section: Discussionmentioning

confidence: 99%

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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“…Similarly, in work from Perks et al (2007) in MCF-7 breast cancer cells and by Uzoh et al (2011) in prostate cancer cells, an integrin-mediated pro-tumourigenic action of IGFBP-2, which occurs via modulation of PTEN has also been suggested.…”

Section: Igfbp-2 Action At the Cell Surface Mediated Via Integrin Recmentioning

confidence: 92%

IGFBP-2 - taking the lead in growth, metabolism and cancer

Yau

Azar

Sabin

et al. 2015

J. Cell Commun. Signal.

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The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.

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Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

et al. 2018

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Measurement of circulating insulin‐like growth factors (IGFs), in particular IGF‐binding protein (IGFBP)‐2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF‐I, IGF‐II, pro‐IGF‐II, IGF bioactivity, IGFBP‐2, ‐3, and pregnancy‐associated plasma protein A (PAPP‐A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993–1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10‐year recurrence‐free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP‐2 and PAPP‐A were independently prognostic [HR biomarker doubling: 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP‐2 plus PAPP‐A. Derived AUCRFS using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification—measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance.

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IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells

Cited by 99 publications

References 31 publications

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

IGFBP-2 - taking the lead in growth, metabolism and cancer

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

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