Summary
Binding of IGF-1 to the type I IGF receptor starts a signalling cascade that plays an important role in regulating cell proliferation, differentiation and apoptosis. The interaction between the IGF-1 and its receptor is mainly regulated by a binding protein, IGFBP3. We studied a CA repeat polymorphism 969 bp upstream of the transcription start site in the IGF-1 gene and an A-202C polymorphism in the IGFBP3 gene and tested their association with breast cancer risk using four case–control series with a total of 787 cases and 900 controls. We did not find any association between the breast cancer risk and the IGF-1 repeat length (19 versus non-19) or the IGFBP3 A-202C polymorphism in the postmenopausal breast cancer series or in women diagnosed for breast cancer under the age of 50. In the familial breast cancer series we observed a non-significantly increased odds-ratio (OR) in homozygotes for the non-19 alleles of the IGF-1 gene (OR 1.51, 95% CI 0.96–2.39, p=0.07). Similarly, in the familial breast cancer series we detected an increased frequency of the IGFBP3 −202C allele carriers (OR 1.50, 95% CI 1.05–2.14, p=0.03). The association was stronger in individuals homozygous for these alleles (OR 3.76, 95% CI 1.44–9.81, p=0.006). Thus, the polymorphisms in the IGF-1 and IGFBP3 genes associated with an increased risk of breast cancer in familial cases carrying the variant alleles.
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Abbreviations
- CI:
-
95% confidence interval
- HWE:
-
Hardy–Weinberg equilibrium
- IGF-1:
-
insulin-like growth factor
- IGFBP3:
-
insulin-like growth factor binding protein
- IGF-1R/IGF-2R:
-
insulin-like growth factor-1/2 receptor
- OR:
-
odds-ratio
- RFLP:
-
restriction fragment length polymorphism
References
P Lichtenstein NV Holm PK Verkasalo A Iliadou J Kaprio M Koskenvuo E Pukkala A Skytthe K Hemminki (2000) ArticleTitleEnvironmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland N Engl J␣Med 343 78–85
K Hemminki C Granstrom (2003) ArticleTitleFamilial breast cancer: scope for more susceptibility genes Breast Cancer Res Treat 82 17–22
J Peto N Collins R Barfoot S Seal W Warren N Rahman DF Easton C Evans J Deacon MR Stratton (1999) ArticleTitleof BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer J Natl Cancer Inst 91 943–949
AC Antoniou PD Pharoah G McMullan NE Day BA Ponder D Easton (2001) ArticleTitleEvidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study Genet Epidemiol 21 1–18
MM de Jong IM Nolte GJ te Meerman WT der Graaf Particlevan JC Oosterwijk JH Kleibeuker M Schaapveld EG Vries Particlede (2002) ArticleTitleGenes other than BRCA1 and BRCA2 involved in breast cancer susceptibility J Med Genet 39 225–242
DL Kleinberg (1998) ArticleTitleRole of IGF-I in normal mammary development Breast Cancer Res Treat 47 201–208
C Laban SA Bustin PJ Jenkins (2003) ArticleTitleThe GH-IGF-I axis and breast cancer Trends Endocrinol Metab 14 28–34
L Jerome L Shiry B Leyland-Jones (2003) ArticleTitleDeregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions Endocr Relat Cancer 10 561–578
MN Pollak ES Schernhammer SE Hankinson (2004) ArticleTitleInsulin-like␣growth factors and neoplasia Nat Rev Cancer 4 505–518
VS Sivaraman H Wang GJ Nuovo CC Malbon (1997) ArticleTitleHyperexpression of mitogen-activated protein kinase in human breast cancer J␣Clin Invest 99 1478–1483
H Yu T Rohan (2000) ArticleTitleRole of the insulin-like growth factor family in cancer development and progression J Natl Cancer Inst 92 1472–1489
R Shi H Yu J McLarty J Glass (2004) ArticleTitleIGF-I and breast cancer: a meta-analysis Int J Cancer 111 418–423
AG Renehan M Zwahlen C Minder ST O’Dwyer SM Shalet M Egger (2004) ArticleTitleInsulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis Lancet 363 1346–1353
M Harrela H Koistinen J Kaprio M Lehtovirta J Tuomilehto J Eriksson L Toivanen M Koskenvuo P Leinonen R Koistinen M Seppala (1996) ArticleTitleGenetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 J Clin Invest 98 2612–2615
TL McCarthy C Ji H Shu S Casinghino K Crothers P Rotwein M Centrella (1997) ArticleTitle17beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures J Biol Chem 272 18132–18139
H Yu BD Li M Smith R Shi HJ Berkel I Kato (2001) ArticleTitlePolymorphic CA repeats in the IGF-I gene and breast cancer Breast Cancer Res Treat 70 117–122
SA Missmer CA Haiman DJ Hunter WC Willett GA Colditz FE Speizer MN Pollak SE Hankinson (2002) ArticleTitleA sequence repeat in the insulin-like growth factor-1 gene and risk of breast cancer Int J␣Cancer 100 332–336
H Jernstrom W Chu D Vesprini Y Tao N Majeed C Deal M Pollak SA Narod (2001) ArticleTitleGenetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk Mol Genet Metab 72 144–154
CJ Rosen ES Kurland D Vereault RA Adler PJ Rackoff WY Craig S Witte J Rogers JP Bilezikian (1998) ArticleTitlebetween serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density J␣Clin Endocrinol Metab 83 2286–2290
C Deal J Ma F Wilkin J Paquette F Rozen B Ge T Hudson M Stampfer M Pollak (2001) ArticleTitleNovel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators J Clin Endocrinol Metab 86 1274–1280
ES Schernhammer SE Hankinson DJ Hunter MJ Blouin MN Pollak (2003) ArticleTitlePolymorphic variation at the −202 locus in IGFBP3: Influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk Int J Cancer 107 60–64
Z Ren Q Cai XO Shu H Cai C Li H Yu YT Gao W Zheng (2004) ArticleTitleGenetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women Cancer Epidemiol Biomarkers Prev 13 1290–1295
K Holli R Valavaara G Blanco V Kataja P Hietanen M Flander E Pukkala H Joensuu (2000) ArticleTitleSafety and efficacy results of a␣randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer.␣Finnish breast cancer group J Clin Oncol 18 3487–3494
Q Jin K Hemminki E Grzybowska R Klaes M Säderberg H Zientek J Rogozinska-Szczepka B Utracka-Hutka J Pamula W Pekala A Försti (2004) ArticleTitlePolymorphisms and haplotype structures in genes for transforming growth factor 1 and its receptors in familial and unselected breast cancers Int J Cancer 112 94–99
A Forsti Q Jin E Grzybowska M Soderberg H Zientek M Sieminska J Rogozinska-Szczepka E Chmielik B Utracka-Hutka K Hemminki (2002) ArticleTitleSex hormone-binding globulin polymorphisms in familial and sporadic breast cancer Carcinogenesis 23 1315–1320
P Vaittinen K Hemminki (2000) ArticleTitleRisk factors and age-incidence relationships for contralateral breast cancer Int J Cancer 88 998–1002
S Garte L Gaspari AK Alexandrie C Ambrosone H Autrup JL Autrup H Baranova L Bathum S Benhamou P Boffetta C Bouchardy K Breskvar J Brockmoller I Cascorbi ML Clapper C Coutelle A Daly M Dell’Omo V Dolzan CM Dresler A Fryer A Haugen DW Hein A Hildesheim A Hirvonen LL Hsieh M Ingelman-Sundberg I Kalina D Kang M Kihara C Kiyohara P Kremers P Lazarus L Le Marchand MC Lechner EM Lieshout Particlevan S London JJ Manni CM Maugard S Morita V Nazar-Stewart K Noda Y Oda FF Parl R Pastorelli I Persson WH Peters A Rannug T Rebbeck A Risch L Roelandt M Romkes D Ryberg J Salagovic B Schoket J Seidegard PG Shields E Sim D Sinnet RC Strange I Stucker H Sugimura J To-Figueras P Vineis MC Yu E Taioli (2001) ArticleTitleMetabolic gene polymorphism frequencies in control populations Cancer Epidemiol Biomarkers Prev 10 1239–1248
K Wagner K Hemminki E Grzybowska R Klaes D Butkiewicz J Pamula W Pekala H Zientek D Mielzynska E Siwinska A Forsti (2004) ArticleTitleThe insulin-like growth factor-1 pathway mediator genes: SHC1 Met300Val shows a protective effect in breast cancer Carcinogenesis 25 2473–2478
K DeLellis S Ingles L Kolonel R McKean-Cowdin B Henderson F Stanczyk NM Probst-Hensch (2003) ArticleTitleIGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort Br J Cancer 88 277–282
ML Slattery W Samowitz K Curtin KN Ma M Hoffman B Caan S Neuhausen (2004) ArticleTitleAssociations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer Cancer Epidemiol Biomarkers Prev 13 1206–1214
E Giovannucci CA Haiman EA Platz SE Hankinson MN Pollak DJ Hunter (2002) ArticleTitleDinucleotide repeat in the insulin-like growth factor-I gene is not related to risk of colorectal adenoma Cancer Epidemiol Biomarkers Prev 11 1509–1510
RS Houlston J Peto (2003) ArticleTitleThe future of association studies of common cancers Hum Genet 112 434–435
AC Antoniou DF Easton (2003) ArticleTitlePolygenic inheritance of breast cancer: Implications for design of association studies Genet Epidemiol 25 190–202
DB Goldstein JN Hirschhorn (2004) ArticleTitleIn genetic control of disease, does ‘race’ matter? Nat Genet 36 1243–1244
L Li MS Cicek G Casey JS Witte (2004) ArticleTitleNo association between genetic polymorphisms in IGF-I and IGFBP-3 and prostate cancer Cancer Epidemiol Biomarkers Prev 13 497–498
AJ Sigurdson M Hauptmann N Chatterjee BH Alexander MM Doody JL Rutter JP Struewing (2004) ArticleTitleKin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair BRCA1 interacting and growth factor genes BMC Cancer 4 9
L Wang T Habuchi N Tsuchiya K Mitsumori C Ohyama K Sato H Kinoshita T Kamoto A Nakamura O Ogawa T Kato (2003) ArticleTitleInsulin-like growth factor-binding protein-3 gene −202 A/C polymorphism is correlated with advanced disease status in prostate cancer Cancer Res 63 4407–4411
K Hemminki A Forsti J Lorenzo Bermejo (2005) ArticleTitleSingle nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events J Carcinog 4 2
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Wagner, K., Hemminki, K., Israelsson, E. et al. Polymorphisms in the IGF-1 and IGFBP3 promoter and the risk of breast cancer. Breast Cancer Res Treat 92, 133–140 (2005). https://doi.org/10.1007/s10549-005-2417-x
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DOI: https://doi.org/10.1007/s10549-005-2417-x