Abstract
Breast cancer prognosis differs among racial and ethnic groups. Though the incidence of breast cancer is lower in African–Americans than in Caucasians, mortality is higher. While socioeconomic, psychosocial, and lifestyle issues are undoubtedly important in such disparities, genetic factors that differ among populations and that are involved in the molecular pathways regulating tumor development may also play roles. In this communication, I summarize recent investigations of the gene encoding the pro-inflammatory cytokine interleukin-6 (IL-6), and suggest that this gene is a susceptibility factor that determines racial and/or ethnic differences in breast cancer survival. Published studies of a G/C polymorphism at nucleotide -174 within the promoter region of the IL-6gene are consistent with this suggestion. This polymorphism alters expression of the cytokine. In addition, allele and genotype frequencies at the -174 site differ dramatically among racial and ethnic groups. Finally, the variant genotypes are associated with alterations in breast cancer survival. In all, these observations argue for additional studies of the IL-6 gene polymorphism as a predisposing genetic factor that contributes to racial and ethnic differences in breast cancer prognosis.
Similar content being viewed by others
References
BJ Trock (1996) ArticleTitleBreast cancer in African American women: epidemiology and tumor biology Breast Cancer Res Treat 40 11–24
FO Ademuyiwa OI Olopade (2003) ArticleTitleRacial differences in genetic factors associated with breast cancer Cancer Metastasis Rev 22 47–53
CP Hunter (2000) ArticleTitleEpidemiology, stage at diagnosis, and tumor biology of breast carcinoma in multiracial and multiethnic populations Cancer 88 1193–1202
CI Li KE Malone JR Daling (2002) ArticleTitleDifferences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older Cancer Epidemiol Biomarkers Prev 11 601–607
SM Shinagawa (2000) ArticleTitleThe excess burden of breast carcinoma in minority and medically underserved communities: application, research, and redressing institutional racism Cancer 88 1217–1223
E Ward A Jemal V Cokkinides GK Singh C Cardinez A Ghafoor M Thun (2004) ArticleTitleCancer disparities by race/ethnicity and socioeconomic status CA Cancer J Clin 54 78–93
AJ Zaloznik (1995) ArticleTitleBreast cancer stage at diagnosis: caucasians versus Afro-Americans Breast Cancer Res Treat 34 195–198
DN Pearlman W Rakowski B Ehrich MA Clark (1996) ArticleTitleBreast cancer screening practices among black, Hispanic, and white women: reassessing differences Am J Prev Med 12 327–337
JW Eley HA Hill VW Chen DF Austin MN Wesley HB Muss RS Greenberg RJ Coates P Correa CK Redmond et al. (1994) ArticleTitleRacial differences in survival from breast cancer Results of the National Cancer Institute Black/White Cancer Survival Study. JAMA 272 947–954
RM Elledge GM Clark GC Chamness CK Osborne (1994) ArticleTitleTumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States J Natl Cancer Inst 86 705–712
JK Wiencke (2004) ArticleTitleImpact of race/ethnicity on molecular pathways in human cancer Nat Rev Cancer 4 79–84
Q Gao S Neuhausen S Cummings M Luce OI Olopade (1997) ArticleTitleRecurrent germ-line BRCA1 mutations in extended African American families with early-onset breast cancer Am J Hum Genet 60 1233–1236
E Taioli J Trachman X Chen P Toniolo SJ Garte (1995) ArticleTitleA CYP1A1 restriction fragment length polymorphism is associated with breast cancer in African–American women Cancer Res 55 3757–3758
C Guillemette RC Millikan B Newman DE Housman (2000) ArticleTitleGenetic polymorphisms in uridine diphospho-glucuronosyltransferase 1Al and association with breast cancer among African Americans Cancer Res 60 950–956
C Guillemette I Vivo ParticleDe SE Hankinson CA Haiman D Spiegelman DE Housman DJ Hunter (2001) ArticleTitleAssociation of genetic polymorphisms in UGT1A1 with breast cancer and plasma hormone levels Cancer Epidemiol Biomarkers Prev 10 711–714
T Hirano (1998) ArticleTitleInterleukin 6 and its receptor: ten years later Int Rev Immunol 16 249–284
CM Leu FH Wong C Chang SF Huang CP Hu (2003) ArticleTitleInterleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways Oncogene 22 7809–7818
K Brocke-Heidrich AK Kretzschmar G Pfeifer C Henze D Loffler D Koczan HJ Thiesen R Burger M Gramatzki F Horn (2004) ArticleTitleInterleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation Blood 103 242–251
M Trikha R Corringham B Klein JF Rossi (2003) ArticleTitleTargeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence Clin Cancer Res 9 4653–4665
J Nakashima M Tachibana Y Horiguchi M Oya T Ohigashi H Asakura M Murai (2000) ArticleTitleSerum interleukin 6 as a prognostic factor in patients with prostate cancer Clin Cancer Res 6 2702–2706
YC Chung YF Chang (2003) ArticleTitleSerum interleukin-6 levels reflect the disease status of colorectal cancer J Surg Oncol 83 222–226
P Bhat-Nakshatri RA Campbell NM Patel TR Newton AJ King MS Marshall S Ali H Nakshatri (2004) ArticleTitleTumour necrosis factor and PI3-kinase control oestrogen receptor alpha protein level and its transrepression function Br J Cancer 90 853–859
D Fishman G Faulds R Jeffery V Mohamed-Ali JS Yudkin S Humphries P Woo (1998) ArticleTitleThe 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 1369–1376
C Belluco F Olivieri M Bonafe S Giovagnetti E Mammano R Scalerta A Ambrosi C Franceschi D Nitti M Lise (2003) ArticleTitle-174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer Clin Cancer Res 9 2173–2176
FA Rivera-Chavez DL Peters-Hybki RC Barber GE O’Keefe (2003) ArticleTitleInterleukin-6 promoter haplotypes and interleukin-6 cytokine responses Shock 20 218–223
CF Terry V Loukaci FR Green (2000) ArticleTitleCooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation J Biol Chem 275 18138–18144
L Christiansen L Bathum K Andersen-Ranberg B Jeune K Christensen (2004) ArticleTitleModest implication of interleukin-6 promoter polymorphisms in longevity Mech Ageing Dev 125 391–395
JL Georges V Loukaci O Poirier A Evans G Luc D Arveiler JB Ruidavets F Cambien L Tiret (2001) ArticleTitleInterleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECITM study Etude Cas-Temoin de 1’Infarctus du Myocarde. J Mol Med 79 300–305
KG Jones DJ Brull LC Brown M Sian RM Greenhalgh SE Humphries JT Powell (2001) ArticleTitleInterleukin-6 (IL-6) and the prognosis of abdominal aortic aneurysms Circulation 103 2260–2265
H Bruunsgaard L Christiansen AN Pedersen M Schroll T Jorgensen BK Pedersen (2004) ArticleTitleThe IL-6 -174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans Exp Gerontol 39 255–261
ED Cox SC Hoffmann BS DiMercurio RA Wesley DM Harlan AD Kirk PJ Blair (2001) ArticleTitleCytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6 Transplantation 72 720–726
A Meenagh F Williams OA Ross C Patterson C Gorodezky M Hammond WA Leheny D Middleton (2002) ArticleTitleFrequency of cytokine polymorphisms in populations from western Europe, Africa, Asia, the Middle East and South America Hum Immunol 63 1055–1061
MI Hassan Y Aschner CH Manning J Xu JL Aschner (2003) ArticleTitleRacial differences in selected cytokine allelic and genotypic frequencies among healthy, pregnant women in North Carolina Cytokine 21 10–16
B Vozarova JM Fernandez-Real WC Knowler L Gallart RL Hanson JD Gruber W Ricart J Vendrell C Richart PA Tataranni et al. (2003) ArticleTitleThe interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians Hum Genet 112 409–413
HN Simhan MA Krohn JM Roberts A Zeevi SN Caritis (2003) ArticleTitleInterleukin-6 promoter -174 polymorphism and spontaneous preterm birth Am J Obstet Gynecol 189 915–918
D Harding S Dhamrait A Millar S Humphries N Marlow A Whitelaw H Montgomery (2003) ArticleTitleIs interleukin-6 -174 genotype associated with the development of septicemia in preterm infants Pediatrics 112 800–803
T Rundek MS Elkind J Pittman B Boden-Albala S Martin SE Humphries SH Juo RL Sacco (2002) ArticleTitleCarotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study Stroke 33 1420–1423
JM Fernandez-Real M Broch J Vendrell C Richart W Ricart (2000) ArticleTitleInterleukin-6 gene polymorphism and lipid abnormalities in healthy subjects J Clin Endocrinol Metab 85 1334–1339
LA Hefler C Grimm S Ackermann S Malur AR Radjabi-Rahat S Leodolter MW Beckmann R Zeillinger H Koelbl CB Tempfer (2003) ArticleTitleAn interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer Cancer Res 63 3066–3068
S Landi V Moreno L Gioia-Patricola E Guino M Navarro J Oca Particlede G Capella F Canzian (2003) ArticleTitleAssociation of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer Cancer Res 63 3560–3566
CB Foster T Lehrnbecher S Samuels S Stein F Mol JA Metcalf K Wyvill SM Steinberg J Kovacs A Blauvelt et al. (2000) ArticleTitleAn IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus Blood 96 2562–2567
W Cozen PS Gill SA Ingles R Masood O Martinez-Maza MF Cockbura WJ Gauderman MC Pike L Bernstein BN Nathwani et al. (2004) ArticleTitleIL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma Blood 103 3216–3221
A DeMichele AM Martin R Mick P Gor L Wray M Klein-Cabral G Athanasiadis T Colligan E Stadtmauer B Weber (2003) ArticleTitleInterleukin-6 -174G->C polymorphism is associated with improved outcome in high-risk breast cancer Cancer Res 63 8051–8056
B Iacopetta F Grieu D Joseph (2004) ArticleTitleThe -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype Br J Cancer 90 419–422
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Berger, F.G. The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality. Breast Cancer Res Treat 88, 281–285 (2004). https://doi.org/10.1007/s10549-004-0726-0
Issue Date:
DOI: https://doi.org/10.1007/s10549-004-0726-0