Lack of Effects of Peroxisome Proliferator-Activated Receptor Gamma Genetic Polymorphisms on Breast Cancer Risk: a Case-Control Study and Pooled Analysis

  • Park, Boyoung (National Cancer Control Institute, National Cancer Center) ;
  • Shin, Aesun (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Kim, Kyee-Zu (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Lee, Yeon-Su (Cancer Genomics Branch, National Cancer Center) ;
  • Hwang, Jung-Ah (Cancer Genomics Branch, National Cancer Center) ;
  • Kim, Yeonju (Cancer Epidemiology Program, University of Hawai'i Cancer Center) ;
  • Sung, Joohon (Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University) ;
  • Yoo, Keun-Young (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Lee, Eun-Sook (Center for Breast Cancer, National Cancer Center)
  • Published : 2014.11.28


A growing body of evidence suggests that the peroxisome proliferator-activated receptor-gamma ($PPAR{\gamma}$) gene may harbor targets for the chemoprevention of breast cancer. However, it is unclear whether polymorphisms in the $PPAR{\gamma}$ gene are associated with the susceptibility of breast cancer. We performed a candidate gene association study between $PPAR{\gamma}$ polymorphisms and breast cancer and a meta-analysis on the association of breast cancer with selected $PPAR{\gamma}$ variants. Six single nucleotide polymorphisms (SNPs) in the $PPAR{\gamma}$ gene were analyzed among 456 breast cancer patients and 461 controls from the National Cancer Center in Korea. Association between the polymorphisms and breast cancer risk were assessed using the Cochrane-Armitage test for trend and a multivariate logistic regression model. Two SNPs, rs3856806 and rs1801282, had been previously analyzed, thus enabling us to perform pooled analyses on their associations with breast cancer susceptibility. Our findings from the candidate gene association study showed no association between the $PPAR{\gamma}$ gene polymorphisms and breast cancer risk. A meta-analysis combining existing studies and our current study also refuted an association of the $PPAR{\gamma}$ gene with breast cancer. Our findings suggest that the $PPAR{\gamma}$ gene may not harbor variants that alter breast cancer susceptibility, although a moderate sample size might have precluded a decisive conclusion.


Supported by : National Cancer Center of Korea


  1. Abbastabar H, Hamidifard P, Roustazadeh A, et al (2013). Relationships between breast cancer and common noncommunicable disease risk factors: an ecological study. Asian Pac J Cancer Prev, 14, 5123-5.
  2. Auwerx J (1999). PPARgamma, the ultimate thrifty gene. Diabetologia, 42, 1033-49.
  3. Barone BB, Yeh HC, Snyder CF, et al (2008). Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA, 300, 2754-64.
  4. Begg CB, Mazumdar M (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics, 50, 1088-101.
  5. Boyle P, Boniol M, Koechlin A, et al (2012). Diabetes and breast cancer risk: a meta-analysis. Br J Cancer, 107, 1608-17.
  6. Calle EE, Kaaks R (2004). Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer, 4, 579-91.
  7. Carmichael AR, Bates T (2004). Obesity and breast cancer: a review of the literature. Breast, 13, 85-92.
  8. Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34.
  9. Fratiglioni L, Wang HX (2007). Brain reserve hypothesis in dementia. J Alzheimers Dis, 12, 11-22.
  10. Gallicchio L, McSorley MA, Newschaffer CJ, et al (2007). Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease. Cancer Detect Prev, 31, 95-101.
  11. Gouda HN, Sagoo GS, Harding AH, et al (2010). The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol, 171, 645-55.
  12. Grommes C, Landreth GE, Heneka MT (2004). Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol, 5, 419-29.
  13. He W (2009). PPARgamma2 polymorphism and human health. PPAR Res, 2009, 849538.
  14. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  15. Justenhoven C, Hamann U, Schubert F, et al (2008). Breast cancer: a candidate gene approach across the estrogen metabolic pathway. Breast Cancer Res Treat, 108, 137-49.
  16. Kaplan J, Cook JA, O'Connor M, et al (2007). Peroxisome proliferator-activated receptor gamma is required for the inhibitory effect of ciglitazone but not 15-deoxy-Delta 12,14-prostaglandin J2 on the NFkappaB pathway in human endothelial cells. Shock, 28, 722-6.
  17. Kim KZ, Shin A, Lee YS, et al (2012). Polymorphisms in adiposity-related genes are associated with age at menarche and menopause in breast cancer patients and healthy women. Hum Reprod, 27, 2193-200.
  18. Koh WP, Yuan JM, Van Den Berg D, et al (2006). Peroxisome proliferator-activated receptor (PPAR) gamma gene polymorphisms and colorectal cancer risk among Chinese in Singapore. Carcinogenesis, 27, 1797-802.
  19. Kotta-Loizou I, Giaginis C, Theocharis S (2012). The role of peroxisome proliferator-activated receptor-gamma in breast cancer. Anticancer Agents Med Chem, 12, 1025-44.
  20. Li Y, Wedren S, Li G, et al (2011). Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer. Breast Cancer Res, 13, 10.
  21. Liu C, Liu L (2011). Polymorphisms in three obesity-related genes (LEP, LEPR, and PON1) and breast cancer risk: a meta-analysis. Tumour Biol, 32, 1233-40.
  22. Lorincz AM, Sukumar S (2006). Molecular links between obesity and breast cancer. Endocr Relat Cancer, 13, 279-92.
  23. Mahdi KM, Nassiri MR, Nasiri K (2013). Hereditary genes and SNPs associated with breast cancer. Asian Pac J Cancer Prev, 14, 3403-9.
  24. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  25. Masud S, Ye S (2003). Effect of the peroxisome proliferator activated receptor-gamma gene Pro12Ala variant on body mass index: a meta-analysis. J Med Genet, 40, 773-80.
  26. Mehta RG, Williamson E, Patel MK, et al (2000). A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions. J Natl Cancer Inst, 92, 418-23.
  27. Memisoglu A, Hankinson SE, Manson JE, et al (2002). Lack of association of the codon 12 polymorphism of the peroxisome proliferator-activated receptor gamma gene with breast cancer and body mass. Pharmacogenetics, 12, 597-603.
  28. Minatoya M, Kutomi G, Asakura S, et al (2013). Equol, adiponectin, insulin levels and risk of breast cancer. Asian Pac J Cancer Prev, 14, 2191-9.
  29. Mueller E, Sarraf P, Tontonoz P, et al (1998). Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell, 1, 465-70.
  30. Pan Z, Trikalinos TA, Kavvoura FK, et al (2005). Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med, 2, 334.
  31. Park SK, Kang D, Kim Y, et al (2009). Epidemiologic characteristics of the breast cancer in Korea. J Korean Med Assoc AID, 52, 937-45.
  32. Paynter RA, Hankinson SE, Colditz GA, et al (2004). No evidence of a role for PPARgamma Pro12Ala polymorphism in endometrial cancer susceptibility. Pharmacogenetics, 14, 851-6.
  33. Peters JM, Shah YM, Gonzalez FJ (2012). The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer, 12, 181-95.
  34. Ronco AL, De Stefani E, Deneo-Pellegrini H, et al (2012). Diabetes, overweight and risk of postmenopausal breast cancer: a case-control study in Uruguay. Asian Pac J Cancer Prev, 13, 139-46.
  35. Sangrajrang S, Chaiwerawattana A, Ploysawang P, et al (2013). Obesity, diet and physical inactivity and risk of breast cancer in Thai women. Asian Pac J Cancer Prev, 14, 7023-7.
  36. Spiegelman BM (1998). PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes, 47, 507-14.
  37. Suzuki T, Hayashi S, Miki Y, et al (2006). Peroxisome proliferator-activated receptor gamma in human breast carcinoma: a modulator of estrogenic actions. Endocr Relat Cancer, 13, 233-50.
  38. Vogel U, Christensen J, Nexo BA, et al (2007). Peroxisome proliferator-activated receptor-gamma2 Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes. Carcinogenesis, 28, 427-34.
  39. Vona-Davis L, Rose DP (2012). Type 2 diabetes and obesity metabolic interactions: common factors for breast cancer risk and novel approaches to prevention and therapy. Curr Diabetes Rev, 8, 116-30.
  40. Wang LQ, Shen W, Xu L, et al (2012). The association between polymorphisms in the leptin receptor gene and risk of breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat, 136, 231-9.
  41. Wu MH, Chu CH, Chou YC, et al (2011). Joint effect of peroxisome proliferator-activated receptor gamma genetic polymorphisms and estrogen-related risk factors on breast cancer risk: results from a case-control study in Taiwan. Breast Cancer Res Treat, 127, 777-84.
  42. Yanhua C, Geater A, You J, et al (2012). Reproductive variables and risk of breast malignant and benign tumours in Yunnan province, China. Asian Pac J Cancer Prev, 13, 2179-84.
  43. Yoo JY, Kim SY, Hwang JA, et al (2012). Association study between folate pathway gene single nucleotide polymorphisms and gastric cancer in Koreans. Genomics Inform, 10, 184-93.
  44. Yoo KY, Kim Y, Park SK, et al (2006). Lifestyle, genetic susceptibility and future trends of breast cancer in Korea. Asian Pac J Cancer Prev, 7, 679-82.

Cited by

  1. Biological underpinnings of breastfeeding challenges: the role of genetics, diet, and environment on lactation physiology vol.311, pp.2, 2016,