IGF-I, IGF binding protein-3 and breast cancer risk: Comparison of 3 meta-analyses

OBJECTIVE: Gross cystic disease (GCD) is the most common benign breast pathology. Although breast cysts are not considered pre-malignant lesions, an increased risk of breast cancer has been reported for patients with type I cysts (Na(+)/K(+)<3). Furthermore, an augmented IGF-I/IGF-binding protein-3 (IGFBP-3) ratio has been described in breast cancer patients. The objective was to evaluate serum IGF-I and binding protein concentrations of type I and type II cyst patients as compared with healthy women. METHODS: Twenty-four patients with type I cysts, 17 with type II cysts and 25 healthy women were evaluated. Serum IGF-I, IGFBP-3 and IGFBP-1 concentrations were measured by IRMA. RESULTS: IGF-I concentrations were significantly higher in sera from patients with type I cysts than in patients with type II cysts. A highly significant decrease of IGFBP-3, the major IGFBP, was found in patients with type I cysts with respect to healthy women, whereas no significant difference was evident between the different cyst types. The IGF-I/IGFBP-3 ratio, an estimate of biologically active IGF-I, was very significantly higher in patients with type I cysts than in both type II patients and healthy women. IGFBP-1 levels were significantly lower in patients with type I than in controls and type II cysts. The IGF-I/IGFBP-1 ratio was significantly higher in patients with type I cysts than in type II bearers and healthy women. Estrogen levels correlated with IGF-I in patients and controls. CONCLUSIONS: The enhanced levels of IGF-I/IGFBP-3 found in patients with type I cysts could eventually be associated with the increased risk of breast cancer described for this group.

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Prostate Cancer Risk in Relation to Insulin-like Growth Factor (IGF)-I and IGF-Binding Protein-3: A Prospective Multiethnic Study

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-07-2694 ◽

2008 ◽

Vol 17 (1) ◽

pp. 252-254 ◽

Cited By ~ 16

Author(s):

M. J. Borugian ◽

J. J. Spinelli ◽

Z. Sun ◽

L. N. Kolonel ◽

I. Oakley-Girvan ◽

...

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Cancer Risk ◽

Binding Protein ◽

Prostate Cancer Risk ◽

Insulin Like Growth Factor ◽

Igf I ◽

Igf Binding ◽

Igf Binding Protein

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Insulin-like growth factor (IGF)-I and IGF-binding protein 3 and the risk of premenopausal breast cancer: A meta-analysis of literature

International Journal of Cancer ◽

10.1002/ijc.20253 ◽

2004 ◽

Vol 111 (2) ◽

pp. 293-297 ◽

Cited By ~ 56

Author(s):

Aravind Sugumar ◽

Yen-Chun Liu ◽

Qiang Xia ◽

Yea-Suk Koh ◽

Keitaro Matsuo

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Binding Protein ◽

Meta Analysis ◽

Insulin Like Growth Factor ◽

Premenopausal Breast Cancer ◽

Igf I ◽

Igf Binding ◽

Igf Binding Protein

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IGF-I; IGF-binding protein-3 and breast cancer risk

Breast Cancer Online ◽

10.1017/s1470903104003001 ◽

2005 ◽

Vol 8 (1) ◽

Author(s):

A. G. Renehan ◽

M. Zwahlen ◽

M. Egger ◽

S. M. Shalet

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Binding Protein ◽

Regulatory Peptides ◽

Cancer Risk Assessment ◽

Conventional View ◽

Increased Risk ◽

Igf I ◽

Igfbp 3

Insulin-like growth factor I (IGF-I) and its main binding protein 3 (IGFBP-3) are multi-regulatory peptides important in tumour cell growth and survival. In the circulation, they occur in large quantities and are readily measured. Across a population, concentrations vary and this may impact on risk of cancers common in western societies. Emerging epidemiological evidence supports the notion that higher levels of IGF-I are associated with increased risk of pre-menopausal, but not post-menopausal, breast cancer. Higher levels of IGFBP-3 may also predict for increased risk of pre-menopausal breast cancer, but this is contrary to the conventional view that this peptide is tumour protective. Nutritional and lifestyle factors, important in breast cancer risk, also inter-relate with circulating levels of IGF-I, but in many circumstances, the relationships are complex. It is becoming increasingly important that the clinical breast oncologist understands the physiology of the IGF system and its potential role in cancer risk assessment and prevention.

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Insulin-like growth factor (IGF)-I, IGF binding protein-3, and breast cancer risk: eight years on

Endocrine Related Cancer ◽

10.1677/erc.1.01219 ◽

2006 ◽

Vol 13 (2) ◽

pp. 273-278 ◽

Cited By ~ 85

Author(s):

Andrew G Renehan ◽

Michelle Harvie ◽

Anthony Howell

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Binding Protein ◽

Meta Analysis ◽

Regulatory Peptides ◽

Insulin Like Growth Factor ◽

Igf I ◽

Igfbp 3

Insulin-like growth factor (IGF)-I, and its main binding protein, IGFBP-3, are multi-functional regulatory peptides of cell growth and survival, attributes important for tumourigenesis. Following seminal work published in 1998, it has been hypothesised that circulating concentrations of these growth factors may be associated with cancer risk. Systematic reviews have reported that high normal range circulating levels of total IGF-I predict for pre- but not post-menopausal breast cancer. By contrast, associations with circulating IGFBP-3 have been inconsistent. A cumulative meta-analysis demonstrates that earlier reported positive associations between IGFBP-3 and pre-menopausal breast cancer risk now seem less clear as large-size cohorts are published. The reasons are complex and include differences in study design, lack of standardisation between assays, and variations in IGFBP-3 proteolytic activity – these are discussed in this commentary.

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Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies

The Lancet Oncology ◽

10.1016/s1470-2045(10)70095-4 ◽

2010 ◽

Vol 11 (6) ◽

pp. 530-542 ◽

Cited By ~ 378

Keyword(s):

Breast Cancer ◽

Data Analysis ◽

Growth Factor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Prospective Studies ◽

Insulin Like Growth Factor ◽

Individual Data ◽

Igf Binding ◽

Igf Binding Protein

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Phosphorylation of Insulin-Like Growth Factor (IGF) Binding Protein-3 by Breast Cancer Cell Membranes Enhances IGF-I Binding

Endocrinology ◽

10.1210/en.2003-0089 ◽

2003 ◽

Vol 144 (9) ◽

pp. 4042-4050 ◽

Cited By ~ 12

Author(s):

Suresh Mishra ◽

Liam J. Murphy

Keyword(s):

Breast Cancer ◽

Cell Membranes ◽

Binding Protein ◽

Cell Monolayer ◽

Cross Linking ◽

Intact Cells ◽

Igf I ◽

Igf Binding ◽

Igf Binding Protein ◽

Igfbp 3

Abstract Cross-linking of nonglycosylated biotinylated IGF binding protein (IGFBP)-3 to T-47D cell membranes identifies complexes with Mr of 32, 50, 70, and 100 kDa. Nonbiotinylated glycosylated IGFBP-3 competed for binding to each of these sites. The 32-kDa band approximated the size of intact nonglycosylated IGFBP-3, but its abundance was enhanced by cross-linking, and it had a more acidic isoelectric point on isoelectric focusing, suggesting that it had undergone phosphorylation. Immobilized IGFBP-3 was phosphorylated in the presence of 32P-γATP by both T-47D cell membranes and by intact cells treated with phenylarsine oxide to inhibit internalization. MCF-7 and COS-1 cells were also able to bind and phosphorylated IGFBP-3. IGF-I inhibited both IGFBP-3 binding to membranes and phosphorylation. However, incubation of T-47D cells with IGFBP-3 enhanced binding of 125I-IGF-I to the cell monolayer indicating that membrane bound IGFBP-3 was able to bind IGF-I. Immobilized IGFBP-3 when phosphorylated by T-47D membranes bound significantly more 125I-IGF-I than nonphosphorylated IGFBP-3. Treatment with alkaline phosphatase significantly reduced 125I-IGF-I binding to phosphorylated immobilized IGFBP-3 and also reduced 125I-IGF-I to T-47D cell monolayers preincubated with IGFBP-3. Phosphorylation of IGFBP-3 by T-47D membranes was partially blocked by inhibitors of both protein kinase A and C. These data demonstrate that binding of IGFBP-3 to breast cancer membranes is accompanied by phosphorylation at the plasma membrane and that both processes are inhibited by IGF-I. However, once phosphorylated the ability of IGFBP-3 to bind IGF-I is enhanced, resulting in increased association of the IGF-I with the cell membrane.

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