Skip to main content

Advertisement

SpringerLink
Log in

Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival

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

Abstract

Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. A modest increase in risk of developing breast cancer was associated with the LEP −2548AA genotype when compared to the LEP −2548GG genotype (age-adjusted OR = 1.30; 95% CI = 1.01–1.66). This association was stronger among postmenopausal women who were obese (OR = 1.86; 95% CI = 0.95–3.64) although the interaction was of borderline statistical significance (P = 0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time = 66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. World Health Organization (WHO) (2000) Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 894 (i–xii): 1–253

  2. Stephenson GD, Rose DP (2003) Breast cancer and obesity: an update. Nutr Cancer 45:1–16

    Article  CAS  PubMed  Google Scholar 

  3. Loi S, Milne RL, Friedlander ML, McCredie MR, Giles GG, Hopper JL, Phillips KA (2005) Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 14:1686–1691

    Article  PubMed  Google Scholar 

  4. Lamar CA, Dorgan JF, Longcope C, Stanczyk FZ, Falk RT, Stephenson HE Jr (2003) Serum sex hormones and breast cancer risk factors in postmenopausal women. Cancer Epidemiol Biomarkers Prev 12:380–383

    CAS  PubMed  Google Scholar 

  5. Schwartz MW, Baskin DG, Kaiyala KJ, Woods SC (1999) Model for the regulation of energy balance and adiposity by the central nervous system. Am J Clin Nutr 69:584–596

    CAS  PubMed  Google Scholar 

  6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  CAS  PubMed  Google Scholar 

  7. Hamilton BS, Paglia D, Kwan AY, Deitel M (1995) Increased obese mRNA expression in omental fat cells from massively obese humans. Nat Med 1:953–956

    Article  CAS  PubMed  Google Scholar 

  8. Baratta M (2002) Leptin—from a signal of adiposity to a hormonal mediator in peripheral tissues. Med Sci Monit 8: RA282–RA292

    Google Scholar 

  9. Rose DP, Gilhooly EM, Nixon DW (2002) Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int J Oncol 21:1285–1292

    CAS  PubMed  Google Scholar 

  10. Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR (2006) Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem 281:26320–26328

    Article  CAS  PubMed  Google Scholar 

  11. Dieudonne MN, Sammari A, Dos Santos E, Leneveu MC, Giudicelli Y, Pecquery R (2006) Sex steroids and leptin regulate 11beta-hydroxysteroid dehydrogenase I and P450 aromatase expressions in human preadipocytes: Sex specificities. J Steroid Biochem Mol Biol 99:189–196

    Article  CAS  PubMed  Google Scholar 

  12. Huang L, Li C (2000) Leptin: a multifunctional hormone. Cell Res 10:81–92

    Article  CAS  PubMed  Google Scholar 

  13. Falk RT, Brinton LA, Madigan MP, Potischman N, Sturgeon SR, Malone KE, Daling JR (2006) Interrelationships between serum leptin, IGF-1, IGFBP3, C-peptide and prolactin and breast cancer risk in young women. Breast Cancer Res Treat 98:157–165

    Article  CAS  PubMed  Google Scholar 

  14. Petridou E, Papadiamantis Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D (2000) Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control 11:383–388

    Article  CAS  PubMed  Google Scholar 

  15. Stattin P, Soderberg S, Biessy C, Lenner P, Hallmans G, Kaaks R, Olsson T (2004) Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat 86:191–196

    Article  CAS  PubMed  Google Scholar 

  16. Coleman DL (1978) Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14:141–148

    Article  CAS  PubMed  Google Scholar 

  17. Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N (1991) Molecular mapping of the mouse ob mutation. Genomics 11:1054–1062

    Article  CAS  PubMed  Google Scholar 

  18. Chagnon YC, Wilmore JH, Borecki IB, Gagnon J, Perusse L, Chagnon M, Collier GR, Leon AS, Skinner JS, Rao DC, Bouchard C (2000) Associations between the leptin receptor gene and adiposity in middle-aged Caucasian males from the HERITAGE family study. J Clin Endocrinol Metab 85:29–34

    Article  CAS  PubMed  Google Scholar 

  19. Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F (2000) Association of the G-2548A polymorphism in the 5’ region of the LEP gene with overweight. Ann Hum Genet 64:391–394

    Article  CAS  PubMed  Google Scholar 

  20. Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS (2001) The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 86:4434–4439

    Article  CAS  PubMed  Google Scholar 

  21. Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P (2002) A polymorphism in the leptin promoter region (−2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res 34:355–359

    Article  CAS  PubMed  Google Scholar 

  22. Gammon MD, Neugut AI, Santella RM, Teitelbaum SL, Britton JA, Terry MB, Eng SM, Wolff MS, Stellman SD, Kabat GC, Levin B, Bradlow HL, Hatch M, Beyea J, Camann D, Trent M, Senie RT, Garbowski GC, Maffeo C, Montalvan P, Berkowitz GS, Kemeny M, Citron M, Schnabe F, Schuss A, Hajdu S, Vincguerra V, Collman GW, Obrams GI (2002) The Long Island Breast Cancer Study Project: description of a multi-institutional collaboration to identify environmental risk factors for breast cancer. Breast Cancer Res Treat 74:235–254

    Article  CAS  PubMed  Google Scholar 

  23. Waksberg J (1978) Sampling methods for random digit dialing. J Am Stat Assoc 73:40–46

    Article  Google Scholar 

  24. Ribeiro R, Araujo AP, Coelho A, Catarino R, Pinto D, Araujo A, Calcada C, Lopes C, Medeiros R (2006) A functional polymorphism in the promoter region of leptin gene increases susceptibility for non-small cell lung cancer. Eur J Cancer 42:1188–1193

    Article  CAS  PubMed  Google Scholar 

  25. Ross JA, Oeffinger KC, Davies SM, Mertens AC, Langer EK, Kiffmeyer WR, Sklar CA, Stovall M, Yasui Y, Robison LL (2004) Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 22:3558–3562

    Article  CAS  PubMed  Google Scholar 

  26. Willett EV, Skibola CF, Adamson P, Skibola DR, Morgan GJ, Smith MT, Roman E (2005) Non-Hodgkin’s lymphoma, obesity and energy homeostasis polymorphisms. Br J Cancer 93:811–816

    Article  CAS  PubMed  Google Scholar 

  27. Hosmer D, Lemeshow S (1989) Applied logistic regression. John Wiley, New York

    Google Scholar 

  28. Allison P (1995) Survival analysis using SAS: a practical guide. SAS, Cary

    Google Scholar 

  29. World Health Organization (WHO) (1995) Report of a WHO expert committee. Physical status: the use and interpretation of anthropometry. WHO, Geneva

  30. Goodwin PJ, Ennis M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N (2005) Is leptin a mediator of adverse prognostic effects of obesity in breast cancer? J Clin Oncol 23:6037–6042

    Article  CAS  PubMed  Google Scholar 

  31. Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331

    Article  CAS  PubMed  Google Scholar 

  32. Miyoshi Y, Funahashi T, Tanaka S, Taguchi T, Tamaki Y, Shimomura I, Noguchi S (2006) High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels. Int J Cancer 118:1414–1419

    Article  CAS  PubMed  Google Scholar 

  33. Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Helal AN, Chouchane L (2006) Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma. BMC Cancer 6:38

    Article  PubMed  Google Scholar 

  34. Ribeiro R, Vasconcelos A, Costa S, Pinto D, Morais A, Oliveira J, Lobo F, Lopes C, Medeiros R (2004) Overexpressing leptin genetic polymorphism (−2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease. Prostate 59:268–274

    Article  CAS  PubMed  Google Scholar 

  35. Skibola CF, Holly EA, Forrest MS, Hubbard A, Bracci PM, Skibola DR, Hegedus C, Smith MT (2004) Body mass index, leptin and leptin receptor polymorphisms, and non-hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 13:779–786

    CAS  PubMed  Google Scholar 

  36. Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin–a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711

    CAS  PubMed  Google Scholar 

  37. Mantzoros CS, Bolhke K, Moschos S, Cramer DW (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80:523–526

    Article  CAS  PubMed  Google Scholar 

  38. Woo HY, Park H, Ki CS, Park YL, Bae WG (2006) Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 237:137–142

    Article  CAS  PubMed  Google Scholar 

  39. Ogawa T, Hirose H, Yamamoto Y, Nishikai K, Miyashita K, Nakamura H, Saito I, Saruta T (2004) Relationships between serum soluble leptin receptor level and serum leptin and adiponectin levels, insulin resistance index, lipid profile, and leptin receptor gene polymorphisms in the Japanese population. Metabolism 53:879–885

    Article  CAS  PubMed  Google Scholar 

  40. Roth MJ, Paltoo DN, Albert PS, Baer DJ, Judd JT, Tangrea J, Taylor PR (2005) Common leptin receptor polymorphisms do not modify the effect of alcohol ingestion on serum leptin levels in a controlled feeding and alcohol ingestion study. Cancer Epidemiol Biomarkers Prev 14:1576–1578

    Article  CAS  PubMed  Google Scholar 

  41. Paracchini V, Pedotti P, Taioli E (2005) Genetics of leptin and obesity: a HuGE review. Am J Epidemiol 162:101–114

    Article  PubMed  Google Scholar 

  42. Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143

    Article  PubMed  Google Scholar 

  43. Cleveland RJ, Eng SM, Abrahamson PE, Britton JA, Teitelbaum SL, Neugut AI, Gammon MD (2007) Weight gain prior to breast cancer diagnosis and survival. Cancer Epidemiol Biomarkers Prev (in press)

  44. Eng SM, Gammon MD, Terry MB, Kushi LH, Teitelbaum SL, Britton JA, Neugut AI (2005) Body size changes in relation to postmenopausal breast cancer among women on Long Island, New York. Am J Epidemiol 162:229–237

    Article  PubMed  Google Scholar 

  45. Gomez JM, Maravall FJ, Gomez N, Navarro MA, Casamitjana R, Soler J (2003) Interactions between serum leptin, the insulin-like growth factor-I system, and sex, age, anthropometric and body composition variables in a healthy population randomly selected. Clin Endocrinol (Oxf) 58:213–219

    Article  CAS  Google Scholar 

Download references

Acknowledgments

For their valuable contributions, the authors thank: members of the Long Island Breast Cancer Network; the participating institutions; our NIH and NIEHS collaborators; members of the External Advisory Committee to the population-based case–control study. We also wish to acknowledge and thank the following LIBCSP collaborators for their contributions with various aspects of our study efforts including: Amanda Golembesky, Ph.D. and Julie Britton, Ph.D. This work is supported by the University of North Carolina Nutrition and Cancer Training grant NCI T32CA72319; National Cancer Institute and the National Institutes of Environmental Health and Sciences grant nos. UO1CA/ES66572, UO1CA66572, P50CA52283, P30ES09089, P30ES10126, and 5T32CA009330-25; and the Breast Cancer Research Fund.

Author information

Authors and Affiliations

  1. Department of Nutrition, School of Public Health, University of North Carolina, CB# 7461, Chapel Hill, NC, 27599-7461, USA

    Rebecca J. Cleveland

  2. Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA

    Marilie D. Gammon

  3. Department of Environmental Health Sciences, Mailman School of Public Heath, Columbia University, New York, NY, USA

    Chang-Min Long & Regina M. Santella

  4. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mia M. Gaudet

  5. Global Epidemiology, Safety, and Risk Management, Pfizer, Inc., New York, NY, USA

    Sybil M. Eng

  6. Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY, USA

    Susan L. Teitelbaum

  7. Department of Epidemiology, Mailman School of Public Heath, Columbia University, New York, NY, USA

    Alfred I. Neugut

Authors
  1. Rebecca J. Cleveland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marilie D. Gammon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang-Min Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mia M. Gaudet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sybil M. Eng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan L. Teitelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alfred I. Neugut
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Regina M. Santella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rebecca J. Cleveland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cleveland, R.J., Gammon, M.D., Long, CM. et al. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival. Breast Cancer Res Treat 120, 745–752 (2010). https://doi.org/10.1007/s10549-009-0503-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0503-1

Keywords

Search

Navigation