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Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood.

Methods

We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor.

Results

Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by traits varied 45–50% between the strata.

Conclusions

Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

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References

  1. American Cancer Society. Breast cancer facts & figures 2015–2016: American Cancer Society, Inc. 2015. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-046381.pdf

  2. Rose DP et al (2012) The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. Endocr Relat Cancer 19(6):R225–R241

    Article  CAS  PubMed  Google Scholar 

  3. Weichhaus M et al (2012) A novel role for insulin resistance in the connection between obesity and postmenopausal breast cancer. Int J Oncol 41(2):745–752

    CAS  PubMed  Google Scholar 

  4. De Marco P et al (2014) GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts. Endocr Relat Cancer 21(5):739–753

    Article  PubMed  Google Scholar 

  5. Muendlein A et al (2013) Association of a common genetic variant of the IGF-1 gene with event-free survival in patients with HER2-positive breast cancer. J Cancer Res Clin Oncol 139(3):491–498

    Article  CAS  PubMed  Google Scholar 

  6. Agurs-Collins T et al (2000) Insulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. Cancer Detect Prev 24(3):199–206

    CAS  PubMed  Google Scholar 

  7. Li BD et al (2001) Free insulin-like growth factor-I and breast cancer risk. Int J Cancer 91(5):736–739

    Article  CAS  PubMed  Google Scholar 

  8. Ferroni P et al (2016) Pretreatment insulin levels as a prognostic factor for breast cancer progression. Oncol 21:1041–1049

    Article  Google Scholar 

  9. Kabat GC et al (2009) Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer 125(11):2704–2710

    Article  CAS  PubMed  Google Scholar 

  10. Gunter MJ et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101(1):48–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sieri S et al (2012) Prospective study on the role of glucose metabolism in breast cancer occurrence. Int J Cancer 130(4):921–929

    Article  CAS  PubMed  Google Scholar 

  12. Parekh N et al (2015) Insulin receptor variants and obesity-related cancers in the Framingham heart study. Cancer Causes Control 26(8):1189–1195

    Article  PubMed  Google Scholar 

  13. Argiles JM et al (2001) Insulin and cancer (review). Int J Oncol 18(4):683–687

    CAS  PubMed  Google Scholar 

  14. Arcidiacono B et al (2012) Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabet Res 2012:789174

    Article  Google Scholar 

  15. Al-Ajmi K et al (2012) Insulin-like growth factor 1 gene polymorphism and breast cancer risk among Arab Omani women: a case-control study. Breast Cancer 6:103–112

    PubMed  PubMed Central  Google Scholar 

  16. DeLellis K et al (2003) IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles multiethnic cohort. Br J Cancer 88(2):277–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Al-Zahrani A et al (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15(1):1–10

    Article  CAS  PubMed  Google Scholar 

  18. Slattery ML et al (2007) Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. Breast Cancer Res Treat 104(2):197–209

    Article  CAS  PubMed  Google Scholar 

  19. Wang Q et al (2014) Genetic and dietary determinants of insulin-like growth factor (IGF)-1 and IGF binding protein (BP)-3 levels among Chinese women. PLoS One 9(10):e108934

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cleveland RJ et al (2006) IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project. Carcinogenesis 27(4):758–765

    Article  CAS  PubMed  Google Scholar 

  21. Quan H et al (2014) IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and cancer risk: a meta-analysis. Cell Biochem Biophys 69(1):169–178

    Article  CAS  PubMed  Google Scholar 

  22. Haiman CA et al (2013) Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. PLoS Genet 9(3):e1003419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dillon LM et al (2015) P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer. Oncogene 34(30):3968–3976

    Article  CAS  PubMed  Google Scholar 

  24. Wang Y et al (2007) Nested case-control study of energy regulation candidate gene single nucleotide polymorphisms and breast cancer. Anticancer Res 27(1B):589–593

    CAS  PubMed  Google Scholar 

  25. Zhang H et al (2013) Association between insulin receptor substrate 1 Gly972Arg polymorphism and cancer risk. Tumour Biol 34(5):2929–2936

    Article  CAS  PubMed  Google Scholar 

  26. Slattery ML et al (2015) MAPK genes interact with diet and lifestyle factors to alter risk of breast cancer: the Breast Cancer Health Disparities Study. Nutr Cancer 67(2):292–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yarden RI et al (2010) Single-nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. Mol Carcinog 49(6):545–555

    CAS  PubMed  Google Scholar 

  28. Iyengar NM et al. (2013) Obesity and inflammation: new insights into breast cancer development and progression. American Society of Clinical Oncology educational book/ASCO American Society of Clinical Oncology Meeting. pp. 46-51

  29. Wasserman L et al (2004) Correlates of obesity in postmenopausal women with breast cancer: comparison of genetic, demographic, disease-related, life history and dietary factors. Int J Obes Relat Metab Disord 28(1):49–56

    Article  CAS  PubMed  Google Scholar 

  30. Werner H (2012) Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene 31(22):2703–2714

    Article  CAS  PubMed  Google Scholar 

  31. Booth FW et al (2012) Lack of exercise is a major cause of chronic diseases. Compr Physiol 2(2):1143–1211

    PubMed  PubMed Central  Google Scholar 

  32. Yaren A et al (2012) Insulin-like growth factor I (Igf-1) gene polymorphism in patients with non-metastatic breast cancer. Gene 503(2):244–247

    Article  CAS  PubMed  Google Scholar 

  33. Pendyala S et al (2011) Diet-induced weight loss reduces colorectal inflammation: implications for colorectal carcinogenesis. Am J Clin Nutr 93(2):234–242

    Article  CAS  PubMed  Google Scholar 

  34. Creighton CJ et al (2012) A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat 132(3):993–1000

    Article  CAS  PubMed  Google Scholar 

  35. Franks SE et al (2012) Transgenic IGF-IR overexpression induces mammary tumors with basal-like characteristics, whereas IGF-IR-independent mammary tumors express a claudin-low gene signature. Oncogene 31(27):3298–3309

    Article  CAS  PubMed  Google Scholar 

  36. Clemmons DR (2007) Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 6(10):821–833

    Article  CAS  PubMed  Google Scholar 

  37. Abbas A et al (2008) Role of IGF-1 in glucose regulation and cardiovascular disease. Expert Rev Cardiovasc Ther 6(8):1135–1149

    Article  CAS  PubMed  Google Scholar 

  38. Anderson GL et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291(14):1701–1712

    Article  CAS  PubMed  Google Scholar 

  39. Morimoto LM et al (2005) Insulin-like growth factor polymorphisms and colorectal cancer risk. Cancer Epidemiol Biomark Prev 14(5):1204–1211

    Article  CAS  Google Scholar 

  40. Rudolph A et al (2013) Colorectal cancer risk associated with hormone use varies by expression of estrogen receptor-beta. Cancer Res 73(11):3306–3315

    Article  CAS  PubMed  Google Scholar 

  41. Campagnoli C et al (2005) Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 96(2):95–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gunter MJ et al (2008) Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res 68(1):329–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rossouw JE et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333

    Article  CAS  PubMed  Google Scholar 

  44. The Women’s Health Initiative Study Group (1998) Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 19(1):61–109

    Article  Google Scholar 

  45. National Cancer Institute. SEER program: comparative staging guide for cancer June 1993

  46. Matthews DR et al (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419

    Article  CAS  PubMed  Google Scholar 

  47. MacKinnon DP et al (2007) Mediation analysis. Annu Rev Psychol 58:593–614

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mackinnon DP et al (1995) A simulation study of mediated effect measures. Multivar Behav Res 30(1):41

    Article  Google Scholar 

  49. Ingelsson E et al (2010) Detailed physiologic characterization reveals diverse mechanisms for novel genetic loci regulating glucose and insulin metabolism in humans. Diabetes 59(5):1266–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dupuis J et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42(2):105–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pechlivanis S et al (2007) Polymorphisms in the insulin like growth factor 1 and IGF binding protein 3 genes and risk of colorectal cancer. Cancer Detect Prev 31(5):408–416

    Article  CAS  PubMed  Google Scholar 

  52. Henningson M et al (2011) IGF1 htSNPs in relation to IGF-1 levels in young women from high-risk breast cancer families: implications for early-onset breast cancer. Fam Cancer 10(2):173–185

    Article  CAS  PubMed  Google Scholar 

  53. Tamimi RM et al (2007) Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study. Breast cancer Res 9(1):R18

    Article  PubMed  PubMed Central  Google Scholar 

  54. Bergman D et al (2013) Insulin-like growth factor 2 in development and disease: a mini-review. Gerontology 59(3):240–249

    Article  CAS  PubMed  Google Scholar 

  55. Boyault S et al (2012) Mutational characterization of individual breast tumors: tP53 and PI3 K pathway genes are frequently and distinctively mutated in different subtypes. Breast Cancer Res Treat 132(1):29–39

    Article  CAS  PubMed  Google Scholar 

  56. Li J et al (2015) Epidermal growth factor receptor and AKT1 gene copy numbers by multi-gene fluorescence in situ hybridization impact on prognosis in breast cancer. Cancer Sci 106(5):642–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wheler JJ et al (2015) Multiple gene aberrations and breast cancer: lessons from super-responders. BMC Cancer 15:442

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hardt O et al (2012) Highly sensitive profiling of CD44+/CD24− breast cancer stem cells by combining global mRNA amplification and next generation sequencing: evidence for a hyperactive PI3K pathway. Cancer Lett 325(2):165–174

    Article  CAS  PubMed  Google Scholar 

  59. Andrade VP et al (2015) Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion. Mol Oncol 9(4):772–782

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Xu Jianfeng and Zheng Siqun Lilly (NorthShore University HealthSystem, Program for Personalized Cancer Care) for assistance with performing the genetic part. Part of the data for this project were provided by The WHI program which is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Program Office: National Heart, Lung, and Blood Institute, Bethesda, MD: Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle, WA: Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: Brigham and Women’s Hospital, Harvard Medical School, Boston, MA: JoAnn E. Manson; MedStar Health Research Institute/Howard University, Washington, DC: Barbara V. Howard; Stanford Prevention Research Center, Stanford, CA: Marcia L. Stefanick; The Ohio State University, Columbus, OH: Rebecca Jackson; University of Arizona, Tucson/Phoenix, AZ: Cynthia A. Thomson; University at Buffalo, Buffalo, NY: Jean Wactawski-Wende; University of Florida, Gainesville/Jacksonville, FL: Marian Limacher; University of Iowa, Iowa City/Davenport, IA: Robert Wallace; University of Pittsburgh, Pittsburgh, PA: Lewis Kuller; Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker. Women’s Health Initiative Memory Study: Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker.

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Authors and Affiliations

  1. Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, 700 Tiverton Ave, 3-264 Factor Building, Los Angeles, CA, 90095, USA

    Su Yon Jung

  2. Department of Occupational Medicine, Epidemiology and Prevention, Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, Great Neck, NY, USA

    Gloria Ho

  3. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    Thomas Rohan & Howard Strickler

  4. Medicine & Nutritional Sciences, University of Arizona Cancer Center, Tucson, AZ, USA

    Jennifer Bea

  5. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Jeanette Papp & Eric Sobel

  6. Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA

    Zuo-Feng Zhang

  7. Division of General Internal Medicine, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Carolyn Crandall

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  1. Su Yon Jung
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  2. Gloria Ho
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Correspondence to Su Yon Jung.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Jung, S.Y., Ho, G., Rohan, T. et al. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with lifestyle factors on postmenopausal breast cancer risk. Breast Cancer Res Treat 164, 475–495 (2017). https://doi.org/10.1007/s10549-017-4272-y

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  • DOI: https://doi.org/10.1007/s10549-017-4272-y

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