Breast Cancer Research and Treatment

, Volume 118, Issue 3, pp 565–574 | Cite as

Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk

  • Daniele Campa
  • James McKay
  • Olga Sinilnikova
  • Anika Hüsing
  • Ulla Vogel
  • Rikke Dalgaard Hansen
  • Kim Overvad
  • Petra Mariann Witt
  • Françoise Clavel-Chapelon
  • Marie-Christine Boutron-Ruault
  • Veronique Chajes
  • Sabine Rohrmann
  • Jenny Chang-Claude
  • Heiner Boeing
  • Eva Fisher
  • Antonia Trichopoulou
  • Dimitrios Trichopoulos
  • Domenico Palli
  • Anna Villarini
  • Carlotta Sacerdote
  • Amalia Mattiello
  • Rosario Tumino
  • Petra H. M. Peeters
  • Carla H. van Gils
  • H. Bas Bueno-de-Mesquita
  • Eiliv Lund
  • María Dolores Chirlaque
  • Núria Sala
  • Laudina Rodriguez Suarez
  • Aurelio Barricarte
  • Miren Dorronsoro
  • Maria-José Sánchez
  • Per Lenner
  • Göran Hallmans
  • Kostas Tsilidis
  • Sheila Bingham
  • Kay-Tee Khaw
  • Valentina Gallo
  • Teresa Norat
  • Elio Riboli
  • Sabina Rinaldi
  • Gilbert Lenoir
  • Sean V. Tavtigian
  • Federico Canzian
  • Rudolf Kaaks
Epidemiology

Abstract

Fatty acid synthase (FAS) is the major enzyme of lipogenesis. It catalyzes the NADPH-dependent condensation of acetyl-CoA and malonyl-CoA to produce palmitic acid. Transcription of the FAS gene is controlled synergistically by the transcription factors ChREBP (carbohydrate response element-binding protein), which is induced by glucose, and SREBP-1 (sterol response element-binding protein-1), which is stimulated by insulin through the PI3K/Akt signal transduction pathway. We investigated whether the genetic variability of the genes encoding for ChREBP, SREBP and FAS (respectively, MLXIPL, SREBF1 and FASN) is related to breast cancer risk and body-mass index (BMI) by studying 1,294 breast cancer cases and 2,452 controls from the European Prospective Investigation on Cancer (EPIC). We resequenced the FAS gene and combined information of SNPs found by resequencing and SNPs from public databases. Using a tagging approach and selecting 20 SNPs, we covered all the common genetic variation of these genes. In this study we were not able to find any statistically significant association between the SNPs in the FAS, ChREBP and SREPB-1 genes and an increased risk of breast cancer overall and by subgroups of age, menopausal status, hormone replacement therapy (HRT) use or BMI. On the other hand, we found that two SNPs in FASN were associated with BMI.

Keywords

Fatty acid synthase Carbohydrate response element-binding protein Sterol response element-binding protein-1 Breast cancer Susceptibility to cancer Body-mass index 

Notes

Acknowledgments

This study was supported by grant W81XWH-04-1-0271 by the US Army Medical Research and Materiel Command. The EPIC study was funded by “Europe Against Cancer” Programme of the European Commission (SANCO); Ligue contre le Cancer (France); Société 3M (France); Mutuelle Générale de l’Education Nationale; Institut National de la Santé et de la Recherche Médicale (INSERM); German Cancer Aid; German Cancer Research Center; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health; the participating regional governments and institutions of Spain; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; Greek Ministry of Health; Greek Ministry of Education; Italian Association for Research on Cancer; Italian National Research Council; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Norwegian Cancer Society. The authors wish to thank Dr Alun Thomas (Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah) for providing assistance with the Java SnpScreen software.

References

  1. 1.
    Augustin LS, Dal Maso L, La Vecchia C et al (2001) Dietary glycemic index and glycemic load, and breast cancer risk: a case–control study. Ann Oncol 12:1533–1538. doi: 10.1023/A:1013176129380 CrossRefPubMedGoogle Scholar
  2. 2.
    Hankinson SE, Willett WC, Colditz GA et al (1998) Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393–1396. doi: 10.1016/S0140-6736(97)10384-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Kaaks R (1996) Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes Control 7:605–625. doi: 10.1007/BF00051703 CrossRefPubMedGoogle Scholar
  4. 4.
    Kaaks R, Lukanova A (2001) Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc 60:91–106. doi: 10.1079/PNS200070 CrossRefPubMedGoogle Scholar
  5. 5.
    Kaaks R, Lukanova A (2002) Effects of weight control and physical activity in cancer prevention: role of endogenous hormone metabolism. Ann N Y Acad Sci 963:268–281PubMedCrossRefGoogle Scholar
  6. 6.
    Muti P, Quattrin T, Grant BJ et al (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 11:1361–1368PubMedGoogle Scholar
  7. 7.
    Toniolo P, Bruning PF, Akhmedkhanov A et al (2000) Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88:828–832. doi: 10.1002/1097-0215(20001201)88:5<828::AID-IJC22>3.0.CO;2-8 CrossRefPubMedGoogle Scholar
  8. 8.
    Kaaks R, Lundin E, Rinaldi S et al (2002) Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden. Cancer Causes Control 13:307–316. doi: 10.1023/A:1015270324325 CrossRefPubMedGoogle Scholar
  9. 9.
    Krajcik RA, Borofsky ND, Massardo S et al (2002) Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer. Cancer Epidemiol Biomarkers Prev 11:1566–1573PubMedGoogle Scholar
  10. 10.
    Li BD, Khosravi MJ, Berkel HJ et al (2001) Free insulin-like growth factor-I and breast cancer risk. Int J Cancer 91:736–739. doi: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1111>3.0.CO;2-# CrossRefPubMedGoogle Scholar
  11. 11.
    Bianchini F, Kaaks R, Vainio H (2002) Overweight, obesity, and cancer risk. Lancet Oncol 3:565–574. doi: 10.1016/S1470-2045(02)00849-5 CrossRefPubMedGoogle Scholar
  12. 12.
    Key T, Appleby P, Barnes I et al (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616PubMedGoogle Scholar
  13. 13.
    Lahmann PH, Schulz M, Hoffmann K et al (2005) Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC). Br J Cancer 93:582–589. doi: 10.1038/sj.bjc.6602763 CrossRefPubMedGoogle Scholar
  14. 14.
    Weiderpass E, Gridley G, Persson I et al (1997) Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer 71:360–363. doi: 10.1002/(SICI)1097-0215(19970502)71:3<360::AID-IJC9>3.0.CO;2-W CrossRefPubMedGoogle Scholar
  15. 15.
    Kuhajda FP, Jenner K, Wood FD et al (1994) Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 91:6379–6383. doi: 10.1073/pnas.91.14.6379 CrossRefPubMedGoogle Scholar
  16. 16.
    da Silva Xavier G, Rutter GA, Diraison F et al (2006) ChREBP binding to fatty acid synthase and L-type pyruvate kinase genes is stimulated by glucose in pancreatic beta-cells. J Lipid Res 47:2482–2491. doi: 10.1194/jlr.M600289-JLR200 CrossRefPubMedGoogle Scholar
  17. 17.
    Andreolas C, da Silva Xavier G, Diraison F et al (2002) Stimulation of acetyl-CoA carboxylase gene expression by glucose requires insulin release and sterol regulatory element binding protein 1c in pancreatic MIN6 beta-cells. Diabetes 51:2536–2545. doi: 10.2337/diabetes.51.8.2536 CrossRefPubMedGoogle Scholar
  18. 18.
    Diraison F, Parton L, Ferre P et al (2004) Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Biochem J 378:769–778. doi: 10.1042/BJ20031277 CrossRefPubMedGoogle Scholar
  19. 19.
    Rufo C, Teran-Garcia M, Nakamura MT et al (2001) Involvement of a unique carbohydrate-responsive factor in the glucose regulation of rat liver fatty-acid synthase gene transcription. J Biol Chem 276:21969–21975. doi: 10.1074/jbc.M100461200 CrossRefPubMedGoogle Scholar
  20. 20.
    Yang YA, Morin PJ, Han WF et al (2003) Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res 282:132–137. doi: 10.1016/S0014-4827(02)00023-X CrossRefPubMedGoogle Scholar
  21. 21.
    Alo PL, Visca P, Trombetta G et al (1999) Fatty acid synthase (FAS) predictive strength in poorly differentiated early breast carcinomas. Tumori 85:35–40. doi: 10.1159/000015275 PubMedGoogle Scholar
  22. 22.
    Milgraum LZ, Witters LA, Pasternack GR et al (1997) Enzymes of the fatty acid synthesis pathway are highly expressed in in situ breast carcinoma. Clin Cancer Res 3:2115–2120PubMedGoogle Scholar
  23. 23.
    Pizer ES, Wood FD, Heine HS et al (1996) Inhibition of fatty acid synthesis delays disease progression in a xenograft model of ovarian cancer. Cancer Res 56:1189–1193PubMedGoogle Scholar
  24. 24.
    Rashid A, Pizer ES, Moga M et al (1997) Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol 150:201–208PubMedGoogle Scholar
  25. 25.
    Shurbaji MS, Kalbfleisch JH, Thurmond TS (1996) Immunohistochemical detection of a fatty acid synthase (OA-519) as a predictor of progression of prostate cancer. Hum Pathol 27:917–921. doi: 10.1016/S0046-8177(96)90218-X CrossRefPubMedGoogle Scholar
  26. 26.
    Alo PL, Visca P, Marci A et al (1996) Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77:474–482. doi: 10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K CrossRefPubMedGoogle Scholar
  27. 27.
    Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7:763–777. doi: 10.1038/nrc2222 CrossRefPubMedGoogle Scholar
  28. 28.
    Swinnen JV, Roskams T, Joniau S et al (2002) Overexpression of fatty acid synthase is an early and common event in the development of prostate cancer. Int J Cancer 98:19–22. doi: 10.1002/ijc.10127 CrossRefPubMedGoogle Scholar
  29. 29.
    Kuhajda FP (2000) Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 16:202–208. doi: 10.1016/S0899-9007(99)00266-X CrossRefPubMedGoogle Scholar
  30. 30.
    Kuhajda FP, Pizer ES, Li JN et al (2000) Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci USA 97:3450–3454. doi: 10.1073/pnas.050582897 CrossRefPubMedGoogle Scholar
  31. 31.
    Pizer ES, Jackisch C, Wood FD et al (1996) Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Cancer Res 56:2745–2747PubMedGoogle Scholar
  32. 32.
    Pizer ES, Thupari J, Han WF et al (2000) Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenografts. Cancer Res 60:213–218PubMedGoogle Scholar
  33. 33.
    Thupari JN, Pinn ML, Kuhajda FP (2001) Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem Biophys Res Commun 285:217–223. doi: 10.1006/bbrc.2001.5146 CrossRefPubMedGoogle Scholar
  34. 34.
    Menendez JA, Colomer R, Lupu R (2005) Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids? Med Hypotheses 64:342–349. doi: 10.1016/j.mehy.2004.07.022 CrossRefPubMedGoogle Scholar
  35. 35.
    Key TJ, Verkasalo PK, Banks E (2001) Epidemiology of breast cancer. Lancet Oncol 2:133–140. doi: 10.1016/S1470-2045(00)00254-0 CrossRefPubMedGoogle Scholar
  36. 36.
    Riboli E, Hunt KJ, Slimani N et al (2002) European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5:1113–1124. doi: 10.1079/PHN2002394 CrossRefPubMedGoogle Scholar
  37. 37.
    Shattuck-Eidens D, Oliphant A, McClure M et al (1997) BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278:1242–1250. doi: 10.1001/jama.278.15.1242 CrossRefPubMedGoogle Scholar
  38. 38.
    Carlson CS, Eberle MA, Rieder MJ et al (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120. doi: 10.1086/381000 CrossRefPubMedGoogle Scholar
  39. 39.
    de Bakker PI, Yelensky R, Pe’er I et al (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223. doi: 10.1038/ng1669 CrossRefPubMedGoogle Scholar
  40. 40.
    Medes G, Thomas A, Weinhouse S (1953) Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res 13:27–29PubMedGoogle Scholar
  41. 41.
    Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227. doi: 10.1038/sj.hdy.6800717 CrossRefPubMedGoogle Scholar
  42. 42.
    Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769. doi: 10.1086/383251 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Daniele Campa
    • 1
    • 2
  • James McKay
    • 3
  • Olga Sinilnikova
    • 4
  • Anika Hüsing
    • 1
  • Ulla Vogel
    • 5
  • Rikke Dalgaard Hansen
    • 6
  • Kim Overvad
    • 7
  • Petra Mariann Witt
    • 7
  • Françoise Clavel-Chapelon
    • 8
  • Marie-Christine Boutron-Ruault
    • 8
  • Veronique Chajes
    • 3
    • 8
  • Sabine Rohrmann
    • 1
  • Jenny Chang-Claude
    • 1
  • Heiner Boeing
    • 9
  • Eva Fisher
    • 9
  • Antonia Trichopoulou
    • 10
  • Dimitrios Trichopoulos
    • 11
  • Domenico Palli
    • 12
  • Anna Villarini
    • 13
  • Carlotta Sacerdote
    • 14
  • Amalia Mattiello
    • 15
  • Rosario Tumino
    • 16
  • Petra H. M. Peeters
    • 17
  • Carla H. van Gils
    • 17
  • H. Bas Bueno-de-Mesquita
    • 18
  • Eiliv Lund
    • 19
  • María Dolores Chirlaque
    • 20
  • Núria Sala
    • 21
  • Laudina Rodriguez Suarez
    • 22
  • Aurelio Barricarte
    • 23
  • Miren Dorronsoro
    • 24
  • Maria-José Sánchez
    • 25
  • Per Lenner
    • 26
  • Göran Hallmans
    • 26
  • Kostas Tsilidis
    • 27
  • Sheila Bingham
    • 28
  • Kay-Tee Khaw
    • 28
  • Valentina Gallo
    • 29
  • Teresa Norat
    • 29
  • Elio Riboli
    • 29
  • Sabina Rinaldi
    • 3
  • Gilbert Lenoir
    • 8
  • Sean V. Tavtigian
    • 3
  • Federico Canzian
    • 1
  • Rudolf Kaaks
    • 1
  1. 1.Department of Cancer EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.University of PisaPisaItaly
  3. 3.International Agency for Research on CancerLyonFrance
  4. 4.Hospices Civils de Lyon/Centre Léon BérardCNRS-Université Claude Bernard UMR5201LyonFrance
  5. 5.National Food InstituteTechnical University of DenmarkCopenhagenDenmark
  6. 6.Danish Cancer SocietyCopenhagenDenmark
  7. 7.Aarhus University HospitalAalborgDenmark
  8. 8.Insitut Gustave RoussyVillejuifFrance
  9. 9.German Institute of Human NutritionPotsdam-RehbrueckeGermany
  10. 10.Department of Hygiene and Epidemiology, Medical SchoolUniversity of AthensAthensGreece
  11. 11.Department of EpidemiologyHavard School of Public HealthBostonUSA
  12. 12.Cancer Research and Prevention Institute (ISPO)FlorenceItaly
  13. 13.Istituto Nazionale dei Tumori (IRCCS)MilanItaly
  14. 14.CPO PiemonteTorinoItaly
  15. 15.Federico II UniversityNaplesItaly
  16. 16.Azienda Ospedaliera “Civile M.P. Arezzo”RagusaItaly
  17. 17.Julius CenterUniversity Medical CenterUtrechtThe Netherlands
  18. 18.National Institute for Public Health and the EnvironmentBilthovenThe Netherlands
  19. 19.Institute of Community Medicine University of TromsøTromsøNorway
  20. 20.Murcia Health CouncilMurciaSpain
  21. 21.Catalan Institute of OncologyBarcelonaSpain
  22. 22.Consejería de Salud y Servicios Sanitarios Principado de AsturiasOviedoSpain
  23. 23.Public Health Institute of NavarraPamplonaSpain
  24. 24.Public Health Department of Gipuzkoa and CIBER de Epidemiología y Salud Pública (CIBERESP)San SebastianSpain
  25. 25.Andalusian School of Public Health and CIBERESPGranadaSpain
  26. 26.Umeå UniversityUmeåSweden
  27. 27.University of OxfordOxfordUK
  28. 28.University of CambridgeCambridgeUK
  29. 29.Imperial CollegeLondonUK

Personalised recommendations