Contrasting effects of IGF binding protein-3 expression in mammary tumor cells and the tumor microenvironment.

IGFBP-3 has both stimulatory and inhibitory effects on cancer progression. The growth of EO771 mammary carcinoma cells as syngeneic tumors in C57BL/6 mice is reduced in Igfbp3-null (BP3KO) mice, suggesting that systemic IGFBP-3 enhances tumor progression. In this study we assessed the growth of EO771 cells expressing human IGFBP-3 in BP3KO mice.

Enhancement of mammary tumour growth by IGFBP-3 involves impaired T cell accumulation.

Epidemiological studies show an association between obesity and poor breast cancer prognosis. We previously demonstrated that global IGFBP-3 deficiency, in IGFBP-3-null mice, resulted in a 50% reduction in mammary tumour growth over 3 weeks relative to tumours in wild-type (WT) C57BL/6 mice. This growth reduction was ameliorated by high fat feeding-induced obesity.

Insulin-like growth factor binding protein-3 links obesity and breast cancer progression.

Obesity is associated epidemiologically with poor breast cancer prognosis, but the mechanisms remain unclear. Since IGF binding protein-3 (IGFBP-3) influences both breast cancer growth and adipocyte maturation, it may impact on how obesity promotes breast oncogenesis. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth.

Soluble M6P/IGFIIR in the circulation.

Soluble M6P/IGFIIR has the potential to be a significant carrier of IGF-II and mannose 6-P proteins in the circulation and play an important role as an antagonist to the cellular receptor. Evidence suggests that soluble receptor plays a role in fetal and childhood growth by opposing the growth stimulatory effects of IGF-II. Maternal serum levels of M6P/IGFIIR are elevated in late pregnancy and the IGF-II:soluble M6P/IGFIIR ratio in cord blood correlates strongly with weight at birth and placental weight suggesting an important role in fetal growth and development.

Inhibition of insulin-like growth factor-binding protein-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGF receptor blockade.

The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor-binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC.

Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells.

Although loss of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells.

Genetic variation in the type 2 insulin-like growth factor receptor gene and disparity in childhood height.

Objective: The type 2 insulin-like growth factor receptor (IGF2R) is thought to regulate insulin-like growth factor-II (IGF-II) bioavailability by degrading it in the lysosomes after uptake. We hypothesised that polymorphisms in the IGF2R gene could alter size at birth and childhood growth.

Design And Methods: The hypothesis was tested in a normal birth cohort (Avon Longitudinal Study of Parents and Children) by genotyping the IGF2R gene gly1619arg polymorphism, which causes a non-conservative amino acid change in the IGF-II binding region, using PCR and restriction fragment length polymorphism analysis.

Increased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo.

The mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF-II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF-IIR on breast cancer cell tumorigenicity.

Insulin-like growth factor-II/mannose 6-phosphate receptor overexpression reduces growth of choriocarcinoma cells in vitro and in vivo.

The IGF-II/mannose-6 phosphate receptor (IGF-II/M6PR) interacts with multiple tumor growth factors, including IGF-II and latent TGFbeta1. The IGF-II/M6PR has been proposed to be a tumor growth suppressor, a hypothesis supported by our previous finding that decreased IGF-II/M6PR expression enhances tumor growth. In this study, we further demonstrate that IGF-II/M6PR overexpression, resulting from cDNA transfection of JEG-3 choriocarcinoma cells, leads to a decreased cellular growth rate in vitro and decreased tumor growth in nude mice.

Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis?

Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood. Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children from achieving a normal height are still unknown.