- Volume 17 Issue 6
Association of Estrogen Receptor Alpha and Interleukin 6 Polymorphisms with Lymphovascular Invasion, Extranodal Extension, and Lower Disease-Free Survival in Thai Breast Cancer Patients
- Sa-Nguanraksa, Doonyapat (Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- Suntiparpluacha, Monthira (Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- Kulprom, Anchalee (Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- Kummalue, Tanawan (Departments of Clinical Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- Chuangsuwanich, Tuenjai (Departments of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- Avirutnan, Panissadee (Division of Dengue Hemorrhagic Fever Research, Department of Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University) ;
- O-Charoenrat, Pornchai (Division of Head, Neck and Breast Surgery, Department of Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University)
- Published : 2016.06.01
Breast cancer is the most frequent type of cancer diagnosed among women worldwide and also in Thailand. Estrogen and estrogen receptors exert important roles in its genesis and progression. Several cytokines have been reported to be involved in the microenvironment that promotes distant metastasis via modulation of immune and inflammatory responses to tumor cells. Estrogen receptor genetic polymorphisms and several cytokines have been reported to be associated with breast cancer susceptibility and aggressiveness. To investigate roles of genetic polymorphisms in estrogen receptor alpha (ESR1) and interleukin 6 (IL6), breast cancer patients and control subjects were recruited from the Division of Head, Neck and Breast Surgery (Siriraj Hospital, Bangkok, Thailand). Polymorphisms in ESR1 (rs3798577) and IL6 (rs1800795 and rs1800797) were evaluated by real-time PCR in 391 breast cancer patients and 79 healthy controls. Associations between genetic polymorphisms and clinicopathological data were determined. There was no association between genetic polymorphisms and breast cancer susceptibility. However the ESR1 rs3798577 CT genotype was associated with presence of lymphovascular invasion (OR=2.07, 95%CI 1.20-3.56, p=0.009) when compared to the TT genotype. IL6 rs1800795 CC genotype was associated with presence of extranodal extension (OR= 2.30, 95%CI 1.23-4.31, p=0.009) when compared to the GG genotype. Survival analysis showed that IL6 rs1800797 AG or AA genotypes were associated with lower disease-free survival. These findings indicate that polymorphisms in ESR1 and IL6 contribute to aggressiveness of breast cancer and may be used to identify high risk patients.
Breast cancer;estrogen receptor;interleukin-6;polymorphisms;prognostic factors
- Zhang L, Gu L, Qian B, et al (2009). Association of genetic polymorphisms of ER-alpha and the estradiol-synthesizing enzyme genes CYP17 and CYP19 with breast cancer risk in Chinese women. Breast Cancer Res Treat, 114, 327-38. https://doi.org/10.1007/s10549-008-9998-0
- Vickers MA, Green FR, Terry C, et al (2002). Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res, 53, 1029-34. https://doi.org/10.1016/S0008-6363(01)00534-X
- Villuendas G, San Millan JL, Sancho J, et al (2002). The -597 G-->A and -174 G-->C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. J Clin Endocrinol Metab, 87, 1134-41.
- Wang Y, He Y, Qin Z, et al (2014). Evaluation of functional genetic variants at 6q25.1 and risk of breast cancer in a Chinese population. Breast Cancer Res, 16, 422. https://doi.org/10.1186/s13058-014-0422-x
- Weidle UH, Klostermann S, Eggle D, et al (2010). Interleukin 6/interleukin 6 receptor interaction and its role as a therapeutic target for treatment of cachexia and cancer. Cancer Genomics Proteomics, 7, 287-302.
- Son BH, Kim MK, Yun YM, et al (2015). Genetic polymorphism of ESR1 rs2881766 increases breast cancer risk in Korean women. J Cancer Res Clin Oncol, 141, 633-45. https://doi.org/10.1007/s00432-014-1849-2
- Myatt SS, Lam EW (2007). The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer, 7, 847-59. https://doi.org/10.1038/nrc2223
- Pan M, Gao SP, Jiang MH, et al (2011). Interleukin 6 promoter polymorphisms in normal Han Chinese population: frequencies and effects on inflammatory markers. J Investig Med, 59, 272-6. https://doi.org/10.2310/JIM.0b013e318206ffad
- Rayoo M, Yan M, Takano EA, et al (2009). Expression of the forkhead box transcription factor FOXP1 is associated with oestrogen receptor alpha, oestrogen receptor beta and improved survival in familial breast cancers. J Clin Pathol, 62, 896-902. https://doi.org/10.1136/jcp.2009.065169
- Rayter Z (1991). Steroid receptors in breast cancer. Br J Surg, 78, 528-35. https://doi.org/10.1002/bjs.1800780506
- Slattery ML, Curtin K, Baumgartner R, et al (2007). IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev, 16, 747-55. https://doi.org/10.1158/1055-9965.EPI-06-0667
- Snoussi K, Strosberg AD, Bouaouina N, et al (2005). Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6) associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw, 16, 253-60.
- Sommer S, Fuqua SA (2001). Estrogen receptor and breast cancer. Semin Cancer Biol, 11, 339-52. https://doi.org/10.1006/scbi.2001.0389
- Jones KG, Brull DJ, Brown LC, et al (2001). Interleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms. Circulation, 103, 2260-5. https://doi.org/10.1161/01.CIR.103.18.2260
- Lambertini E, Penolazzi L, Giordano S, et al (2003). Expression of the human oestrogen receptor-alpha gene is regulated by promoter F in MG-63 osteoblastic cells. Biochem J, 372, 831-9. https://doi.org/10.1042/bj20021633
- Liu Z, Wang Z, Xiao Y, et al (2015). Association between the interleukin-6 gene polymorphisms and renal cancer risk. Immunol Lett, 164, 125-8. https://doi.org/10.1016/j.imlet.2015.03.001
- Fishman D, Faulds G, Jeffery R, et al (1998). The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest, 102, 1369-76. https://doi.org/10.1172/JCI2629
- Fox SB, Brown P, Han C, et al (2004). Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas. Clin Cancer Res, 10, 3521-7. https://doi.org/10.1158/1078-0432.CCR-03-0461
- Gao SP, Liang S, Pan M, et al (2014). Interleukin-6 genotypes and serum levels in Chinese Hui population. Int J Clin Exp Med, 7, 2851-7.
- Global Burden of Disease Cancer C, Fitzmaurice C, Dicker D, et al (2015). The Global Burden of Cancer 2013. JAMA Oncol, 1, 505-27. https://doi.org/10.1001/jamaoncol.2015.0735
- Gonzalez-Zuloeta Ladd AM, Arias Vasquez A, Witteman J, et al (2006). Interleukin 6 G-174 C polymorphism and breast cancer risk. Eur J Epidemiol, 21, 373-6. https://doi.org/10.1007/s10654-006-9005-1
- Hefler LA, Grimm C, Lantzsch T, et al (2005). Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women. Clin Cancer Res, 11, 5718-21. https://doi.org/10.1158/1078-0432.CCR-05-0001
- Heikkila K, Ebrahim S, Lawlor DA (2008). Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer, 44, 937-45. https://doi.org/10.1016/j.ejca.2008.02.047
- Humphries SE, Luong LA, Ogg MS, et al (2001). The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J, 22, 2243-52. https://doi.org/10.1053/euhj.2001.2678
- DeMichele A, Martin AM, Mick R, et al (2003). Interleukin-6-174G-->C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res, 63, 8051-6.
- Anghel A, Raica M, Narita D, et al (2010). Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer. Neoplasma, 57, 306-15.
- Ataie-Kachoie P, Pourgholami MH, Morris DL (2013). Inhibition of the IL-6 signaling pathway: a strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev, 24, 163-73. https://doi.org/10.1016/j.cytogfr.2012.09.001
- Attasara P, Buasom R 2010. Hospital-based cancer registry 2009, Bangkok, Information Technology Division, National Cancer Institute,.
- Belluco C, Olivieri F, Bonafe M, et al (2003). -174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res, 9, 2173-6.
- Brull DJ, Montgomery HE, Sanders J, et al (2001). Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol, 21, 1458-63. https://doi.org/10.1161/hq0901.094280
- Bruunsgaard H, Christiansen L, Pedersen AN, et al (2004). The IL-6 -174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans. Exp Gerontol, 39, 255-61. https://doi.org/10.1016/j.exger.2003.10.012
- Chen CH, Gong M, Yi QT, et al (2015). Role of interleukin-6 gene polymorphisms in the development of prostate cancer. Genet Mol Res, 14, 13370-4. https://doi.org/10.4238/2015.October.26.34
- Cherel M, Campion L, Bezieau S, et al (2009). Molecular screening of interleukin-6 gene promoter and influence of -174G/C polymorphism on breast cancer. Cytokine, 47, 214-23. https://doi.org/10.1016/j.cyto.2009.06.011
- DeMichele A, Gray R, Horn M, et al (2009). Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. Cancer Res, 69, 4184-91. https://doi.org/10.1158/0008-5472.CAN-08-2989