Top

Published in:

01-08-2014 | Original Paper

Increased TNF α, IL-6 and ErbB2 mRNA expression in peripheral blood leukocytes from breast cancer patients

Authors: Majed S. Alokail, Nasser M. Al-Daghri, Abdul Khader Mohammed, Paul Vanhoutte, Amal Alenad

Published in: Medical Oncology | Issue 8/2014

Abstract

Obesity has been associated with increased incidence and mortality of breast cancer. The precise relation between obesity and breast cancer is yet to be determined, with few studies linking them with altered serum levels adipokines and inflammatory cytokines. The relevance of the expression of genes encoding for adipokines and inflammatory cytokines in the peripheral blood and their contribution to obesity and breast cancer has not been fully investigated. We aim to identify potential transcriptional biomarkers in blood samples that may assist to underpin the link between obesity and breast cancer. Therefore, have investigated whether or not the expression levels, of selected genes [tumor necrosis factor-α (TNFα), interleukin 6 (IL-6), adiponectin, leptin, C-reactive protein (CRP), parathyroid hormone (PTH), tumor protein 53 (TP53) and erythroblastic leukemia viral oncogene 2 (ErbB2)] were altered in blood samples of lean, overweight/obese and breast cancer subjects. Blood samples were obtained from 37 lean, 19 overweight/obese and 12 breast cancer patients. Real-time polymerase chain reaction assays were performed to detect TNFα, IL-6, adiponectin, leptin, CRP, PTH, TP53 and ErbB2 gene transcripts. Transcript levels of TNFα were significantly higher by 1.4-fold and 2.1-fold in blood cells of overweight/obese and breast cancer patients, respectively, compared with lean control subjects. Transcript levels of IL-6 were significantly higher by 2.3-fold in blood cells from breast cancer patients compared with lean control subjects with normal body mass index, and no significant difference was found in the expression level of IL-6 transcripts between overweight/obese and lean control subjects. The ErbB2 transcript levels were significantly higher by 4.72-fold compared to lean control subjects and were also significantly higher compared to overweight/obese subjects. Breast cancer and obesity are associated with altered mRNA levels of cytokines and tumor marker in peripheral blood.

Loureiro ML, Nayga RM. International dimensions of obesity and overweight related problems: an economics perspective. Am J Agric Econ. 2005;87(5):1147–53.CrossRef

Al-Nozha MM, Al-Mazrou YY, Al-Maatouq MA, Arafah MR, Khalil MZ, Khan NB, et al. Obesity in Saudi Arabia. Saudi Med J. 2005;26(5):824–9.PubMed

Engström G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgärde F. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes. 2003;52(8):2097–101.PubMedCrossRef

Festa A, D’Agostino R Jr, Williams K, Karter A, Mayer-Davis E, Tracy R, et al. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord J Int Assoc Study Obes. 2001;25(10):1407.CrossRef

Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745–51.PubMed

Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab. 2000;85(9):3338–42.PubMed

Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women. JAMA J Am Med Assoc. 2003;289(14):1799–804.CrossRef

Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol. 2003;148(5):535–42.PubMedCrossRef

Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110(12):1564–71.PubMedCrossRef

10.

DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clinicians. 2011;61:408.CrossRef

11.

El Saghir NS, Khalil MK, Eid T, El Kinge AR, Charafeddine M, Geara F, et al. Trends in epidemiology and management of breast cancer in developing Arab countries: a literature and registry analysis. Int J Surg. 2007;5(4):225–33.PubMedCrossRef

12.

Harvie M, Howell A. Energy balance adiposity and breast cancer–energy restriction strategies for breast cancer prevention. Obes Rev. 2006;7(1):33–47.PubMedCrossRef

13.

Lithgow D, Covington C. Chronic inflammation and breast pathology: a theoretical model. Biol Res Nurs. 2005;7(2):118–29.PubMedCrossRef

14.

Han C, Zhang HT, Du L, Liu X, Jing J, Zhao X, et al. Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine. 2005;26(1):19–24.PubMedCrossRef

15.

Tworoger SS, Eliassen AH, Kelesidis T, Colditz GA, Willett WC, Mantzoros CS, et al. Plasma adiponectin concentrations and risk of incident breast cancer. J Clin Endocrinol Metab. 2007;92(4):1510–6.PubMedCrossRef

16.

Heikkilä K, Ebrahim S, Lawlor DA. A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health. 2007;61(9):824–33.PubMedCentralPubMedCrossRef

17.

Almquist M, Bondeson AG, Bondeson L, Malm J, Manjer J. Serum levels of vitamin D, PTH and calcium and breast cancer risk—a prospective nested case–control study. Int J Cancer. 2010;127(9):2159–68.PubMedCrossRef

18.

Slamon DJGW, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12.PubMedCrossRef

19.

Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253(5015):49–53.PubMedCrossRef

20.

Burczynski ME, Dorner AJ. Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics. 2006;7(2):187–202.PubMedCrossRef

21.

Friedwald W, Levy R, Frederickson D. Estimation of plasma low density lipoprotein cholesterol concentration with use of preparative ultracentrifugation. Clin Chem. 1972;18:499–509.

22.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta] [Delta] CT method. Methods. 2001;25(4):402–8.PubMedCrossRef

23.

Albuquerque K, Price M, Badley R, Jonrup I, Pearson D, Blamey R, et al. Pre-treatment serum levels of tumour markers in metastatic breast cancer: a prospective assessment of their role in predicting response to therapy and survival. Eur J Surg Oncol. 1995;21(5):504–9.PubMedCrossRef

24.

Zhang G, Adachi I. Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res. 1999;19(2B):1427.PubMed

25.

Bozcuk H, Uslu G, Samur M, YIldIz M, Özben T, Özdogan M, et al. Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine. 2004;27(2–3):58–65.CrossRef

26.

Ahmad R, Al-Mass A, Atizado V, Al-Hubail A, Al-Ghimlas F, Al-Arouj M, et al. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J Inflamm (Lond). 2012;9:48.CrossRef

27.

Alokail MS, Al-Daghri NM, Al-Attas OS, Hussain T. Combined effects of obesity and type 2 diabetes contribute to increased breast cancer risk in premenopausal women. Cardiovasc Diabetol. 2009;8(1):33.PubMedCentralPubMedCrossRef

28.

Hill VK, Ricketts C, Bieche I, Vacher S, Gentle D, Lewis C, et al. Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. Cancer Res. 2011;71(8):2988–99.PubMedCrossRef

29.

Sánchez J, Priego T, Picó C, Ahrens W, De Henauw S, Fraterman A, et al. Blood cells as a source of transcriptional biomarkers of childhood obesity and its related metabolic alterations: results of the IDEFICS study. J Clin Endocrinol Metab. 2012;97:E648.PubMedCrossRef

30.

O’Rourke R, Kay T, Lyle E, Traxler S, Deveney C, Jobe B, et al. Alterations in peripheral blood lymphocyte cytokine expression in obesity. Clin Exp Immunol. 2006;146(1):39–46.PubMedCentralPubMedCrossRef

31.

Purohit A, Newman S, Reed M. The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res. 2002;4(2):65–9.PubMedCentralPubMedCrossRef

32.

Berclaz G, Li S, Price K, Coates A, Castiglione-Gertsch M, Rudenstam CM, et al. Body mass index as a prognostic feature in operable breast cancer: the international breast cancer study group experience. Ann Oncol. 2004;15(6):875–84.PubMedCrossRef

33.

Kamel M, Shouman S, El-Merzebany M, Kilic G, Veenstra T, Saeed M, et al. Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells. J Cancer. 2012;3:310.PubMedCentralPubMedCrossRef

34.

de Mello VDF, Kolehmainen M, Schwab U, Mager U, Laaksonen DE, Pulkkinen L, et al. Effect of weight loss on cytokine messenger RNA expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome. Metabolism. 2008;57(2):192–9.PubMedCrossRef

35.

Sullivan NJ. Interleukin-6 as a potential mediator of breast cancer progression and non-melanoma skin carcinogenesis. Columbus: Ohio State University; 2009.

36.

Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117(12):3988–4002.PubMedCentralPubMedCrossRef

37.

Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-α-positive human breast cancer. FASEB J. 2007;21(13):3763–70.PubMedCrossRef

38.

Tsiotra P, Tsigos C, Yfanti E, Anastasiou E, Vikentiou M, Psarra K, et al. Visfatin, TNF-alpha and IL-6 mRNA expression is increased in mononuclear cells from type 2 diabetic women. Horm Metab Res. 2007;39(10):758–63.PubMedCrossRef

39.

Kempf K, Haltern G, Futh R, Herder C, Muller-Scholze S, Gulker H, et al. Increased TNF-alpha and decreased TGF-beta expression in peripheral blood leukocytes after acute myocardial infarction. Horm Metab Res. 2006;38(5):346.PubMedCrossRef

40.

Swiatoniowski G, Dabrowska M, Kłaniewski T, Molenda W. Erb-2 overexpression in breast cancer]. Ginekol Pol. 2003;74(4):332.PubMed

41.

Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol. 2007;19(2):124–34.PubMedCrossRef

Title: Increased TNF α, IL-6 and ErbB2 mRNA expression in peripheral blood leukocytes from breast cancer patients
Authors: Majed S. Alokail
Nasser M. Al-Daghri
Abdul Khader Mohammed
Paul Vanhoutte
Amal Alenad
Publication date: 01-08-2014
Publisher: Springer US
Published in: Medical Oncology / Issue 8/2014
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-014-0038-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Increased TNF α, IL-6 and ErbB2 mRNA expression in peripheral blood leukocytes from breast cancer patients

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2014

Thyroid carcinoma after treatment for malignancies in childhood and adolescence: from diagnosis through follow-up

Expression pattern of Notch intracellular domain (NICD) and Hes-1 in preneoplastic and neoplastic human oral squamous epithelium: their correlation with c-Myc, clinicopathological factors and prognosis in Oral cancer

Which tyrosine kinase inhibitor should be recommended as initial treatment for non-small cell lung cancer patients with EGFR mutations?

Gene therapy for unresectable hepatocellular carcinoma using recombinant human adenovirus type 5

Prognostic value of the microRNA-29 family in patients with primary osteosarcomas

Positive immunohistochemical expression of bcl-2 in hormone-independent breast carcinomas is associated with a greater lymph node involvement and poor outcome

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page