Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II

Earlier data suggest that the relationship between circulating insulin-like growth factor I (IGF-I) levels and breast cancer risk differs according to menopausal status. We evaluated the association between IGF levels as well as the primary regulator of IGF-I production, growth hormone (GH), and breast cancer risk in the Nurses’ Health Study II (NHS II) cohort, a large cohort of primarily premenopausal women. We conducted a case-control study nested within the prospective NHS II cohort. Plasma concentrations of IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and GH were measured in blood samples collected between 1996 and 1999. Totally 317 women were identified who had a diagnosis of invasive or in situ breast cancer between the date of blood collection and June 1 2003; 75% of these women were premenopausal at blood collection. To each of the 317 women, two controls were age-matched for a total of 634 controls. We used conditional logistic regression models to estimate the relative risk of breast cancer. Overall, plasma IGF-I, IGFBP-1, IGFBP-3, and GH levels were not associated with breast cancer risk (relative risks, top vs bottom quartile; IGF-I, 0.98, 95% confidence interval (CI), 0.69–1.39; IGFBP-1, 0.95, 95% CI, 0.63–1.41; IGFBP-3, 1.10, 95% CI, 0.78–1.54; GH, 1.09, 95% CI, 0.82–1.46). These risks were similar for premenopausal women of age 45 years or less. Further adjustment for additional breast cancer risk factors did not change these estimates. In conclusion, circulating IGF-I, IGFBP-1, IGFBP-3, and GH levels appear to have no important association with breast cancer risk in a large cohort of premenopausal women.

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Faculty Opinions recommendation of IGF-I, IGFBP-3 and breast cancer risk in women: The European Prospective Investigation into Cancer and Nutrition (EPIC).

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14205.471705 ◽

2006 ◽

Author(s):

Pagona Lagiou

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Igf I ◽

Igfbp 3 ◽

Prospective Investigation

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Comment on Association between Insulin-Like Growth Factor-I (IGF-I) and Bone Mineral Density: Further Evidence Linking IGF-I to Breast Cancer Risk

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.5.5677-4 ◽

1999 ◽

Vol 84 (5) ◽

pp. 1760-1761 ◽

Cited By ~ 3

Author(s):

He Yu

Keyword(s):

Breast Cancer ◽

Bone Mineral Density ◽

Growth Factor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Bone Mineral ◽

Insulin Like Growth Factor ◽

Mineral Density ◽

Factor I ◽

Igf I

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Circulating amino acids, amino acid metabolites, dipeptides, and other cationic metabolites and risk of breast cancer

10.1101/2020.09.01.20185835 ◽

2020 ◽

Author(s):

Oana A Zeleznik ◽

Raji Balasubramanian ◽

Yibai Zhao ◽

Lisa Frueh ◽

Sarah Jeanfavre ◽

...

Keyword(s):

Breast Cancer ◽

Amino Acid ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Premenopausal Women ◽

Elastic Net ◽

P Value ◽

Blood Collection ◽

Cancer Risk Factors ◽

Breast Cancer Risk Factors

Background: Breast cancer is the most common malignancy among women in the United States, with more than 250,000 cases diagnosed each year. Metabolomics, which reflect the aggregate effects of genetics and the environment on an individual's metabolic state, can shed light on biochemical pathways involved in susceptibility to breast cancer. We investigated associations between pre-diagnostic circulating amino acids-related metabolites and subsequent risk of breast cancer among predominantly premenopausal women. Methods: In 1996-1999, 29,611 women (average age, 44 years) in the Nurses' Health Study II donated blood samples. Between blood collection and June 2011, 1057 women were diagnosed with breast cancer (average of 8 years after blood collection). Women were predominately premenopausal at the time of blood collection. 207 amino acid and amino acid-related metabolites were profiled with LC-MS/MS. Conditional logistic regression (CLR) was used to estimate odds ratios (ORs) of breast cancer and 95% confidence intervals (CIs). Multivariable analyses evaluating the joint association of all metabolites with breast cancer risk were based on CLR with a lasso penalty (Lasso), CLR with an elastic net penalty (Elastic Net), and Random Forests. We used FDR to account for testing multiple hypotheses. Results: Eleven metabolites were associated with breast cancer risk in CLR models, after adjustment for multiple comparisons (p value < 0.05 and q value < 0.20; creatine had q value > 0.20), 6 of which remained significant after adjustment for breast cancer risk factors (p-value<0.05). Higher levels of six metabolites, including 2-aminohippuric acid, DMGV, kynurenic acid, N2, N2-dimethylguanosine, phenylacetyl glutamine and piperine, were associated with lower breast cancer risk (e.g., piperine: ORsimple (95%CI) = 0.85 (0.78-0.93); ORadjusted (95%CI)=0.84 (0.77-0.92)). Higher levels of asparagine, creatine and 3 lipids (C20:1 LPC, C34:3 PC plasmalogen, C40:7 PE plasmalogen) were associated with increased breast cancer risk (e.g., C40:7 PE plasmalogen ORsimple (95%CI) = 1.14 (1.05-1.25); ORadjusted (95%CI) = 1.11 (1.01-1.22)). Piperine, 2-aminohippuric acid, C40:7 PE plasmalogen and creatine were also selected in multivariable modeling approaches (Lasso, Elastic Net, and Random Forests). Conclusions: Two diet-related metabolites, piperine (responsible for the pungency of pepper) and 2-aminohippuric acid (the glycine conjugate of the tryptophan metabolite anthranilic acid) were inversely associated, while C40:7 PE plasmalogen (a highly unsaturated glycerophospholipid and key component of the lipid bilayer of cells) was positively associated with breast cancer risk among predominately premenopausal women, independent of established breast cancer risk factors. Further validation of the specific metabolite associations with breast cancer risk in independent cohorts is warranted.

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Lipoprotein and metabolite associations to breast cancer risk in the HUNT2 study

10.1101/2021.10.08.21264729 ◽

2021 ◽

Author(s):

Julia Debik ◽

Hartmut Schaefer ◽

Trygve Andreassen ◽

Feng Wang ◽

Fang Fang ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Premenopausal Women ◽

Health Study ◽

Breast Cancer Patients ◽

Serum Samples ◽

Lipoprotein Subfractions ◽

Premenopausal Breast Cancer

Background: The aim of this study was to investigate if serum lipoprotein and metabolic profiles of healthy women can predict the risk of developing breast cancer in the future, and to gain a better understanding of the etiology of the disease. Methods: From a cohort of 70 000 participants within the Trondelag Health Study (HUNT study), we identified 1199 women who developed breast cancer within a 22 year follow-up period. Through a nested case-control study design, future breast cancer patients and matching controls (n = 2398) were analysed. Using nuclear magnetic resonance (NMR) spectroscopy, 28 metabolites and 112 lipoprotein subfractions were quantified from prediagnostic serum samples. Logistic regression was used to test metabolites and lipoprotein subfractions for associations with breast cancer risk and partial least-squares discriminant analysis (PLS-DA) models were built to predict future disease. Results: Among premenopausal women (554 cases) 14 lipoprotein subfractions were associated with long-term breast cancer risk. In specific, different subfractions of VLDL particles (in particular VLDL-2, VLDL-3 and VLDL-4) were inversely associated with breast cancer. For total VLDL: apolipoprotein B, cholesterol, free cholesterol and phospholipids were inversely associated with premenopausal breast cancer risk, and in addition total and HDL-4 triglycerides. No significant association was found in postmenopausal women. Conclusions: We identified several associations between lipoprotein subfractions and long-term risk of breast cancer in premenopausal women. Inverse associations between several VLDL subfractions and breast cancer risk were found, revealing an altered metabolism in the endogenous lipid pathway many years prior to a breast cancer diagnosis.

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Association of polymorphisms and haplotypes in the human growth hormone 1 (GH1) gene with breast cancer

Endocrine Related Cancer ◽

10.1677/erc.1.01073 ◽

2005 ◽

Vol 12 (4) ◽

pp. 917-928 ◽

Cited By ~ 13

Author(s):

K Wagner ◽

K Hemminki ◽

E Israelsson ◽

E Grzybowska ◽

R Klaes ◽

...

Keyword(s):

Breast Cancer ◽

Growth Hormone ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Promoter Region ◽

Human Growth ◽

Proximal Promoter ◽

Joint Analysis ◽

Nucleotide Polymorphisms ◽

Igf I

The growth hormone 1 (GH1)/insulin-like growth factor I (IGF-I) axis plays an important role in the development of breast cancer. By binding to its receptor, GH1 stimulates the production of IGF-I and its binding protein IGFBP3, resulting in the regulation of cell proliferation, differentiation and apoptosis. The GH1 gene expression is regulated by a highly polymorphic proximal promoter and a distal locus control region (LCR) 14.5 kb upstream of the gene. We investigated the effect of single nucleotide polymorphisms (SNPs) in the LCR and in the promoter region and an intron 4 SNP (IVS4+90 T/A) on breast cancer risk in a large cohort of Polish and German familial breast cancer cases and controls. SNPs in the LCR did not show an influence on breast cancer risk, either alone or in haplotypes. Three SNPs in the promoter region (G-340T, A-68G/C and A-63T/C) showed an increased and four SNPs (A-137G, G-119T, G-93delG and T-4G) a decreased allele frequency in the cases compared with the controls. Two of the SNPs (A-137G and G-93delG) lead to a decreased breast cancer risk among the minor allele carriers in the joint analysis of the two populations (odds ratio (OR) 0.62, 95% confidence interval (95% CI) 0.44–0.89, P=0.01 and OR 0.65, 95% CI 0.47–0.90, P=0.01, respectively). Haplotype analysis with these seven promoter SNPs revealed a protective association (OR 0.61, 95% CI 0.37–1.00, P=0.04) for the haplotype GAGdAAT, containing the G-93delG variant allele, which in the single analysis already showed a protective effect. The effect was marginally stronger in combination with the LCR GC haplotype (OR 0.49, 95% CI 0.23–1.01, P=0.04).

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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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Circulating amino acids and amino acid-related metabolites and risk of breast cancer among predominantly premenopausal women

npj Breast Cancer ◽

10.1038/s41523-021-00262-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Oana A. Zeleznik ◽

Raji Balasubramanian ◽

Yibai Zhao ◽

Lisa Frueh ◽

Sarah Jeanfavre ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Amino Acids ◽

Amino Acid ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Kynurenic Acid ◽

Conditional Logistic Regression ◽

Premenopausal Women ◽

Health Study

AbstractKnown modifiable risk factors account for a small fraction of premenopausal breast cancers. We investigated associations between pre-diagnostic circulating amino acid and amino acid-related metabolites (N = 207) and risk of breast cancer among predominantly premenopausal women of the Nurses’ Health Study II using conditional logistic regression (1057 cases, 1057 controls) and multivariable analyses evaluating all metabolites jointly. Eleven metabolites were associated with breast cancer risk (q-value < 0.2). Seven metabolites remained associated after adjustment for established risk factors (p-value < 0.05) and were selected by at least one multivariable modeling approach: higher levels of 2-aminohippuric acid, kynurenic acid, piperine (all three with q-value < 0.2), DMGV and phenylacetylglutamine were associated with lower breast cancer risk (e.g., piperine: ORadjusted (95%CI) = 0.84 (0.77–0.92)) while higher levels of creatine and C40:7 phosphatidylethanolamine (PE) plasmalogen were associated with increased breast cancer risk (e.g., C40:7 PE plasmalogen: ORadjusted (95%CI) = 1.11 (1.01–1.22)). Five amino acids and amino acid-related metabolites (2-aminohippuric acid, DMGV, kynurenic acid, phenylacetylglutamine, and piperine) were inversely associated, while one amino acid and a phospholipid (creatine and C40:7 PE plasmalogen) were positively associated with breast cancer risk among predominately premenopausal women, independent of established breast cancer risk factors.

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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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