Effect of type 1 insulin-like growth factor receptor targeted therapy on chemotherapy in human cancer and the mechanisms involved

Hopkins, A.; Crowe, Philip; Yang, Jialin

doi:10.1007/s00432-010-0792-0

Cited by 20 publications

(13 citation statements)

References 74 publications

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“…In breast cancer, with the evidence that IGF1R is involved in resistance to endocrine therapy, anti-human epidermal growth factor receptor 2 (Her2) therapy and chemotherapy, targeting the IGF1R has particular appeal [11,12]. So far, phase II studies with IGF1R inhibitors indicated favorable toxicity profiles and promising activity [13]. As no biomarkers are available yet to select patients who have the potential to benefit from IGF1R-targeted therapy, there is an urgent need to develop a good understanding of the factors contributing to it.…”

Section: Introductionmentioning

confidence: 98%

Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression

Ibusuki

Yamamoto

et al. 2011

Breast Cancer Res Treat

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Insulin-like growth factor-1 receptor (IGF1R) plays a key role in the initiation and progression of breast cancer. However, its prognostic relevance to breast cancer patients has long been a matter of debate. In a series of 325 primary invasive breast cancer patients, we performed a comprehensive analysis of IGF1R at the levels of gene copy number, mRNA expression and protein expression. The relationship between the IGF1R status and the clinicopathological characteristics and prognosis was evaluated. IGF1R mRNA levels not only correlated with protein expression, but also were significantly associated with several clinicopathological parameters and prognosis. Patients with low nuclear grade, negative axillary lymph nodes, positive hormone receptor, negative Her2, negative Ki67, and luminal subtype tumors showed higher expression levels of IGF1R mRNA, which was shown to be a significant univariate parameter for both relapse-free survival and breast cancer-specific survival (BCSS) as well as a significant multivariate parameter for BCSS. IGF1R protein expression showed an association with a prolonged BCSS in univariate analysis. In contrast, IGF1R gene copy number was not correlated with mRNA and protein expression, and harbored no prognostic value. When studied in the luminal tumor subtype groups, IGF1R mRNA level was still significantly associated with a better BCSS. Overall, our data indicated a correlation between IGF1R mRNA expression and protein expression in primary breast cancer. In particular, IGF1R mRNA expression appeared to be a good prognostic marker both in the entire cohort and in the luminal subtype group. These data may serve as background information for IGF1R-targeted therapy.

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Section: Introductionmentioning

confidence: 98%

Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression

Ibusuki

Yamamoto

et al. 2011

Breast Cancer Res Treat

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“…Despite their structural similarities, the two receptors have varying functions. The insulin receptor is pivotal in the maintenance of glucose homeostasis, while the IGFR1 regulates cellular proliferation, differentiation, migration and protection from apoptosis (Hopkins et al, 2010). IGF1 and at a reduced affinity IGF2, can both bind to IGFR1.…”

Section: Introductionmentioning

confidence: 99%

“…Type 1 IGF receptor (IGFR1) is structurally homologous to the insulin receptor, exhibiting 84% amino acid similarity (Hopkins et al, 2010). Despite their structural similarities, the two receptors have varying functions.…”

Section: Introductionmentioning

confidence: 99%

Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells

Kleiman

Keats

Chan

et al. 2013

Experimental and Molecular Pathology

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“…Though EMTs are primarily a mechanism for tissue patterning during development, this cellular process has also been observed in adult tissue as an explanation for the conversion of various epithelial cells to a mesenchymal, and ultimately metastatic phenotype. While many studies have investigated TGF-β's role in regulating EMTs, most studies describing biological effects of TGF-β have been carried out in vitro using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted in vivo as a latent complex [9]. While much is known about TGF-β signaling in comparison, the mechanism of TGF-β activation, and its relationship to IGF-1 in breast cancer metastasis, is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition

Walsh

Damjanovski

2011

Cell Commun Signal

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IntroductionTGF-β signaling has been extensively studied in many developmental contexts, amongst which is its ability to induce epithelial to mesenchymal transitions (EMT). EMTs play crucial roles during embryonic development and have also come under intense scrutiny as a mechanism through which breast cancers progress to become metastatic. Interestingly, while the molecular hallmarks of EMT progression (loss of cell adhesion, nuclear localization of β-catenin) are straightforward, the cellular signaling cascades that result in an EMT are numerous and diverse. Furthermore, most studies describing the biological effects of TGF-β have been performed using high concentrations of active, soluble TGF-β, despite the fact that TGF-β is produced and secreted as a latent complex.MethodsMCF-7 breast cancer cells treated with recombinant IGF-1 were assayed for metalloproteinase activity and invasiveness through a matrigel coated transwell invasion chamber. IGF-1 treatments were then followed by the addition of latent-TGF-β1 to determine if elevated levels of IGF-1 together with latent-TGF-β1 could cause EMT.ResultsResults showed that IGF-1 - a molecule known to be elevated in breast cancer is a regulator of matrix metalloproteinase activity (MMP) and the invasive potential of MCF-7 breast cancer cells. The effects of IGF-1 appear to be mediated through signals transduced via the PI3K and MAPK pathways. In addition, increased IGF-1, together with latent TGF-β1 and active MMPs result in EMT.ConclusionsTaken together our data suggest a novel a link between IGF-1 levels, MMP activity, TGF-β signaling, and EMT in breast cancer cells.

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Effect of type 1 insulin-like growth factor receptor targeted therapy on chemotherapy in human cancer and the mechanisms involved

Cited by 20 publications

References 74 publications

Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression

Insulin-like growth factor-1 receptor gene expression is associated with survival in breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression

Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells

IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition

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