Browse > Article
http://dx.doi.org/10.7314/APJCP.2013.14.11.6813

Overall Survival and Clinicopathological Characteristics of Patients with Breast Cancer in Relation to the Expression Pattern of HER-2, IL-6, TNF-α and TGF-β1  

Tripsianis, Gregory (Laboratory of Medical Statistics, Medical School, Democritus University of Thrace)
Papadopoulou, Evropi (Laboratory of Biochemistry, Medical School, Democritus University of Thrace)
Romanidis, Konstantinos (Second Department of Surgery, Medical School, Democritus University of Thrace)
Katotomichelakis, Michael (Department of Otorhinolaryngology, Medical School, Democritus University of Thrace)
Anagnostopoulos, Kostas (Laboratory of Biochemistry, Medical School, Democritus University of Thrace)
Kontomanolis, Emmanuel (Department of Obstetrics and Gynecology, Medical School, Democritus University of Thrace)
Botaitis, Sotirios (Second Department of Surgery, Medical School, Democritus University of Thrace)
Tentes, Ioannis (Laboratory of Biochemistry, Medical School, Democritus University of Thrace)
Kortsaris, Alexandros (Laboratory of Biochemistry, Medical School, Democritus University of Thrace)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.11, 2013 , pp. 6813-6820 More about this Journal
Abstract
The present study was conducted to investigate the prognostic significance of co-expression patterna of HER-2, IL-6, TNF-a and TGF-${\beta}1$ in breast cancer, by correlating the number of markers with positive expression with clinicopathological characteristics indicative of tumor progression and overall survival. One hundred thirty consecutive patients with primary breast cancer were prospectively included and evaluated. Serum concentrations of the above markers were measured by ELISA. Median split was used to subdivide patients with marker positive or negative expression. The presence of ${\geq}3$ positive markers was independently associated with extended lymph node (>3) involvement (aOR, 11.94, p=0.001) and lymphovascular invasion (aOR, 12.04, p=0.018), increasing the prognostic significance of each marker considered separately. Additional prognostic information regarding survival was also provided; as the number of positive markers increased, a gradually reduction of survival time was observed. In addition, patients with 4 positive markers had significantly shorter survival (25 vs 39 months, p=0.006) and a more than 4 fold increased risk of death (aHR, 4.35, p=0.003) compared to patients with 3 positive markers. Our findings suggest that the coexpression pattern of these four markers could be used clinically as a useful marker for tumor extension and outcome of breast cancer.
Keywords
HER-2; IL-6; TNF-${\alpha}$; TGF-${\beta}1$; breast cancer; survival;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Kong Y, Dai S, Xie X, et al (2012). High serum HER2 extracellular domain levels: correlation with a worse disease-free survival and overall survival in primary operable breast cancer patients. J Cancer Res Clin Oncol, 138, 275-84.   DOI
2 Kostler W, Schwab B, Singer C, et al (2004). Monitoring serum Her-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res, 10, 1618-24.   DOI   ScienceOn
3 Lin W, Karin M (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest, 117, 1175-83.   DOI   ScienceOn
4 Lipton A, Ali S, Leitzel K, et al (2002). Elevated serum Her-2/neu level predicts decreased response to hormone therapyin metastatic breast cancer. J Clin Oncol, 20, 1467-72.   DOI   ScienceOn
5 Locksley R, Killeen N, Lenardo M (2001). The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell, 104, 487-501.   DOI   ScienceOn
6 Ma L, Yang H, Han X, et al (2012). Relationship between serum HER2 extracellular domain levels, tissue HER2 expression, and clinico-pathological parameters in early stage breast cancer. Chinese Med J, 125, 4104-10.
7 MacEwan D (2002). TNF receptor subtype signalling: differences and cellular consequences. Cell Signal, 14, 477-92.   DOI   ScienceOn
8 Massague J, Cheifetz S, Laiho M, et al (1992). Transforming growth factor-beta. Cancer Surv, 12, 81-103.
9 Moore R, Owens D, Stamp G, et al (1999). Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med, 5, 828-31.   DOI   ScienceOn
10 Nicolini A, Carpi A, Rossi G (2006). Cytokines in breast cancer. Cytokine Growth Factor Rev, 17, 325-37.   DOI   ScienceOn
11 Panis C, Herrera A, Victorino V, Aranome A, Cecchini R (2013). Screening of circulating TGF-$\beta$ levels and its clinicopathological significance in human breast cancer. Anticancer Res, 33, 737-42.
12 Papadopoulou E, Anagnostopoulos K, Tripsianis G, et al (2008a). Evaluation of predictive and prognostic significance of serum TGF-beta1 levels in breast cancer according to HER-2 codon 655 polymorphism. Neoplasma, 55, 229-38.
13 Papadopoulou E, Tripsianis G, Anagnostopoulos K, et al (2008b). The influence of serum HER-2 levels and HER-2 codon 655 polymorphism on breast cancer outcome. Neoplasma, 55, 113-21.
14 Papadopoulou E, Tripsianis G, Anagnostopoulos K, et al (2010). Significance of serum tumor necrosis factor-alpha and its interaction with HER-2 codon 655 polymorphism on breast cancer outcome. Int J Biol Markers, 25, 126-35.
15 Parker C (2004). Active surveillance: towards a new paradigm in the management of early prostate cancer. Lancet Oncol, 5, 101-6.   DOI   ScienceOn
16 Perera M, Tsang C, Distel R, et al (2010). TGF-beta1 interactome: metastasis and beyond. Cancer Genomics Proteomics, 7, 217-29.
17 Ravishankaran P, Karunanithi R (2011). Clinical significance of preoperative serum interleukin-6 and Creactive protein level in breast cancer patients. World J Surg Oncol, 9, 18.   DOI   ScienceOn
18 Reiss M, Barcellos-Hoff M (1997). Transforming growth factor-beta in breast cancer: a working hypothesis. Breast Cancer Res Treat, 45, 81-95.   DOI   ScienceOn
19 Rustin G (2003). Use of CA 125 to assess response to new agents in ovarian cancer trials. J Clin Oncol, 21, 187-93.   DOI   ScienceOn
20 Ross J, Fletcher J, Bloom K, et al (2004). Targeted therapy in breast cancer: the HER-2/neu, gene and protein. Mol Cell Proteomics, 3, 379-98.   DOI   ScienceOn
21 Samuel S, Hurta R, Kondaiach P, et al (1992). Autocrine induction of tumor protease production and invasion by a metallothionen-regulated TGF-$\beta$1. EMBO J, 11, 1599-605.
22 Samy N, Ragab H, El Maksoud N, Shaalan M (2010). Prognostic significance of serum Her2/neu, BCL2, CA15-3 and CEA in breast cancer patients: a short follow-up. Cancer Biomark, 6, 63-72.   DOI
23 Sharif M, Mamoon N, Mushtaq S, Khadim M (2010). Age related association of Her-2/neu with prognostic markers in female breast carcinoma. J Coll Physicians Surg Pak, 20, 590-4.
24 Sharma R, Anker S (2002). Cytokines, apoptosis and cachexia: the potential for TNF antagonism. Int J Cardiol, 85, 161-71.   DOI   ScienceOn
25 Sheen-Chen S, Chen H, Sheen C, et al (2001). Serum levels of Transforming growth factor-$\beta$1 in patients with breast cancer. Arch Surg, 136, 937-9.   DOI   ScienceOn
26 Siegel P, Massague J (2003). Cytostatic and apoptotic actions of TGF-$\beta$1 in homeostasis and cancer. Cancer, 3, 807-20.
27 Thomson A, Lotze M (2003). The cytokine handbook" (4th ed), Academic Press, London.
28 Todorovi.-Rakovi. N (2008). TGF-$\beta$ and HER2/ErbB2 and Breast Cancer Progres-sion. In "Transforming Growth Factor-$\beta$ in Cancer Therapy, Volume II," Humana Press, 141-51.
29 Ueki N, Nakazato M, Ohkawa T, et al (1992). Excessive production of transforming growth factor-$\beta$1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim Biophys Acta, 1137, 189-96.   DOI   ScienceOn
30 Tripsianis G, Papadopoulou E, Botaitis S, et al (2012). A Diagnostic and prognostic significance of serum IL-6 levels in breast cancer. JP J Biostatistics, 1-2, 59-77.
31 Vilcek J, Lee T (1991). Tumour necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem, 266, 7313-16.
32 Wang S (2011). The functional crosstalk between HER2 tyrosine kinase and TGF-$\beta$ signaling in breast cancer malignancy. J Signal Transduction, 2011, 804236.
33 Wang X, Shao X, Chen Z, et al (2012). Circulating HER2 extracellular domain (ECD) levels are associated with progression-free survival in metastatic breast cancer patients. Cancer Res, 72.
34 Yarden Y, Sliwkowski M (2001). Untangling the ErbB signaling network. Nat Rev Mol Cell Biol, 2, 127-37.   DOI   ScienceOn
35 Zhou B, Hu M, Miller S, et al (2000). HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kB pathway. J Biol Chem, 275, 8027-31.   DOI   ScienceOn
36 Ali S, Leitzel K, Chinchilli V, et al (2002). Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer. Clin Chem, 48, 1314-20.
37 Aggarwal B, Vijayalekshmi R, Sung B (2009). Targeting infl ammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res, 15, 425-30.   DOI   ScienceOn
38 Al-Hassan A, Al-Ghurabi B, Al-Karkhi I (2012). Prognostic value of proinflammatory cytokines in breast cancer. J Biomol Res Ther, 1, 104.
39 Ali H, Mahdi N, Al-Jowher M (2012). Serum ig and cytokine levels in women with breast cancer before and after mastectomy. Med J Islamic World Acad-emy Sci, 20, 121-9.
40 Alsuhail R (2008). Serum level of interleukin 6 and tumor necrosis factor in Iraqi breast cancer patients. MMJ, 7, 34-6.
41 Alvarez B, Quinn L, Busquets S, et al (2002). Tumor necrosis factor-alpha exerts interleukin-6-dependent and independent effects on cultured skeletal muscle cells. Biochim Biophys Acta, 1542, 66-72.   DOI   ScienceOn
42 Auvinen P, Lipponen P, Johansson R, et al (1995). Prognostic significance of TGF-$\beta$1 and TGF-$\beta$2 expressions in female breast cancer. Anticancer Res, 15, 2627-32.
43 Azizun-Nisa, Bhurgri Y, Raza F, Kayani N (2008). Comparison of ER, PR & HER-2/neu (C-erb B 2) reactivity pattern with histologic grade, tumor size and lymph node status in breast cancer. Asian Pac J Cancer Prev, 9, 553-6.
44 Badache A, Hynes N (2001). Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res, 61, 383-91.
45 Bewick M, Chadderton T, Conlon M, et al (1999). Expression of cerbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support. Bone Marrow Transplant, 24, 377-84.   DOI
46 Balkwill F (2002). Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev, 13, 135-41.   DOI   ScienceOn
47 Balkwill F (2009). Tumour necrosis factor and cancer. Nat Rev Cancer, 9, 361-71.   DOI   ScienceOn
48 Ben-Baruch A (2003). Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res, 5, 31-6.   DOI
49 Bloom H, Richardson W (1957). Histological grading and prognosis in breast cancer. Br J Cancer, 11, 359-77.   DOI   ScienceOn
50 Bromberg J, Wrzeszczynska M, Devgan G, et al (1999). Stat3 as an oncogene. Cell, 98, 295-303.   DOI   ScienceOn
51 Carney W, Neumann R, Lipton A, et al (2003). Potential utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer. Clin Chem, 49, 1579-98.   DOI   ScienceOn
52 Chavey C, Bibeau F, Gourgou-Bourgade S, et al (2007). Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res, 9, 15.
53 Chod J, Zavadova E, Halaska M (2008). Preoperative transforming growth factor-beta 1 (TGF-beta 1) plasma levels in operable breast cancer patients. Eur J Gynaecol Oncol, 29, 613-6.
54 Duffy M (2001). Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful? Clin Chem, 47, 624-30.
55 Colomer R, Llombard-Cussac A, Lluch A, et al (2004). Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER-2 extracellular domain. Ann Oncol, 15, 201-6.   DOI   ScienceOn
56 Dave H, Shah M, Trivedi S, Shukla S (2012). Prognostic utility of circulating transforming growth factor beta 1 in breast cancer patients. Int J Biol Markers, 27, 53-9.   DOI   ScienceOn
57 Derynck R, Goeddel D, Ulrich A, et al (1987). Synthesis of messenger RNAs for transforming growth factors $\alpha$ and $\beta$ and the epidermal growth factor receptor by human tumors. Cancer Res, 47, 707-12.
58 Duffy M (2002). Urokinase plasminogen activator and its inhibitor, PAI-1, as prognostic markers in breast cancer: from pilot to level 1 evidence studies. Clin Chem, 48, 1194-7.
59 Duffy M (2006). Serum tumor markers in breast cancer: are they of clinical value? Clin Chem, 52, 345-51.   DOI   ScienceOn
60 Elston C, Ellis I, Pinder S (1999). Pathological prognostic factors in breast cancer. Crit Rev Oncol Haematol, 31, 209-23.   DOI   ScienceOn
61 Esteva F, Cheli C, Fritsche H, et al (2005). Clinical utility of serum HER-2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Cancer Res, 7, 436-43.   DOI   ScienceOn
62 Fehm T, Jager W, Kramer S, et al (2004). Prognostic significance of serum HER2 and CA15-3 at the time of diagnosis of metastatic breast cancer. Anticancer Res, 24, 1987-92.
63 Grivennikov S, Karin M (2011). Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis, 70, 104-8.   DOI   ScienceOn
64 Fisher P, Hancock B (1997). Gestational trophoblastic disease and their treatment. Cancer Treat Rev, 23, 1-16.   DOI   ScienceOn
65 Grivennikov S, Greten F, Karin M (2010). Immunity, inflammation, and cancer. Cell, 140, 883-99.   DOI   ScienceOn
66 Grivennikov S, Karin M (2010). Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev, 21, 11-9.   DOI   ScienceOn
67 Harris L, Liotcheva V, Broadwater G, et al (2001). Comparison of methods of meas-uring HER-2 in metastatic breast cancer patients treated with high-dose chemotherapy. J Clin Oncol, 19, 1698-706.   DOI
68 Heikkila K, Ebrahim S, Lawlor D (2008). Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer, 44, 937-45.   DOI   ScienceOn
69 Isaacs C, Stearns V, Hayes D (2001). New prognostic factors for breast cancer. Semin Oncol, 28, 53-67.   DOI
70 Kayacan O, Karnak D, Beder S, et al (2006). Impact of TNF-alpha and IL-6 levels on development of cachexia in newly diagnosed NSCLC patients. Am J Clin Oncol, 29, 328-35.   DOI   ScienceOn
71 Knupfer H, Preiss R (2007). Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat, 102, 129-35.   DOI   ScienceOn