nach oben

Breast Cancer Research and Treatment

Erschienen in:

01.02.2012 | Preclinical study

COX2 overexpression is a prognostic marker for Stage III breast cancer

verfasst von: Hee Sung Kim, Hyeong-Gon Moon, Wonshik Han, Cha Kyung Yom, Woo Ho Kim, Jun Ho Kim, Dong-Young Noh

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2012

Einloggen, um Zugang zu erhalten

Abstract

To determine the significance of (Cyclooxygenase 2) COX2 for clinical outcome in breast cancer, we analyzed the correlation between COX2 overexpression and survival in 687 patients with invasive breast cancer. Cytoplasmic immunoreactivity of COX2 was determined as positive in 325 of 687 (47.3%) invasive breast cancers. COX2 positivity was significantly correlated with high histologic grade, negative estrogen receptor (ER), high Ki67, luminal B and triple-negative tumors, Bcl2 negativity, and p53 overexpression. In univariate analysis, COX2 overexpression resulted in significantly shorter relapse-free survival (RFS) [hazard ratio (HR) 1.487, 95% CI 1.035–2.110, P = 0.032]. Multivariate analysis revealed no significant association between COX2 overexpression and either overall survival (OS) or RFS. Kaplan–Meier analysis of the whole patient group showed significantly reduced RFS in patients with high COX2 expression, compared to those that did not overexpress COX2 (91 vs. 162 months, P = 0.031). Stratified subgroup analysis by TNM stage disclosed marked differences in OS and RFS rates in Stage III patients. We observed a significant association of COX2 overexpression with shorter RFS in the ER-negative subgroup of Stage III patients. The results show that COX2 overexpression is a significant unfavorable prognostic factor in Stage III breast cancer, and provide selective criteria for COX2 inhibitor combinations for invasive breast cancer therapy.

Barnes NL, Warnberg F, Farnie G, White D, Jiang W, Anderson E, Bundred NJ (2007) Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br J Cancer 96:575–582. doi:10.1038/sj.bjc.6603593 PubMedCrossRef

Mazhar D, Ang R, Waxman J (2006) COX inhibitors and breast cancer. Br J Cancer 94:346–350. doi:10.1038/sj.bjc.6602942 PubMedCrossRef

Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocr Relat Cancer 8:97–114PubMedCrossRef

Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635PubMed

Denkert C, Winzer KJ, Muller BM, Weichert W, Pest S, Kobel M, Kristiansen G, Reles A, Siegert A, Guski H, Hauptmann S (2003) Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97:2978–2987. doi:10.1002/cncr.11437 PubMedCrossRef

Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC (2002) Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol 55:429–434PubMedCrossRef

O’Connor JK, Avent J, Lee RJ, Fischbach J, Gaffney DK (2004) Cyclooxygenase-2 expression correlates with diminished survival in invasive breast cancer treated with mastectomy and radiotherapy. Int J Radiat Oncol Biol Phys 58:1034–1040. doi:10.1016/j.ijrobp.2003.08.032 PubMedCrossRef

Park K, Han S, Shin E, Kim HJ, Kim JY (2006) Cox-2 expression on tissue microarray of breast cancer. Eur J Surg Oncol 32:1093–1096. doi:10.1016/j.ejso.2006.05.010 PubMedCrossRef

Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massague J (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–1009. doi:10.1038/nature08021 PubMedCrossRef

10.

Singh B, Berry JA, Shoher A, Ayers GD, Wei C, Lucci A (2007) COX-2 involvement in breast cancer metastasis to bone. Oncogene 26:3789–3796. doi:10.1038/sj.onc.1210154 PubMedCrossRef

11.

Subbaramaiah K, Dannenberg AJ (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24:96–102. doi:10.1016/S0165-6147(02)00043-3 PubMedCrossRef

12.

Liu B, Qu L, Tao H (2010) Cyclo-oxygenase 2 up-regulates the effect of multidrug resistance. Cell Biol Int 34:21–25. doi:10.1042/CBI20090129

13.

Kalalinia F, Elahian F, Behravan J (2010) Potential role of cyclooxygenase-2 on the regulation of the drug efflux transporter ABCG2 in breast cancer cell lines. J Cancer Res Clin Oncol. doi:10.1007/s00432-010-0893-9 PubMed

14.

Dang CT, Dannenberg AJ, Subbaramaiah K, Dickler MN, Moasser MM, Seidman AD, D’Andrea GM, Theodoulou M, Panageas KS, Norton L, Hudis CA (2004) Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin Cancer Res 10:4062–4067. doi:10.1158/1078-0432.CCR-03-0463 PubMedCrossRef

15.

Canney PA, Machin MA, Curto J (2006) A feasibility study of the efficacy and tolerability of the combination of exemestane with the COX-2 inhibitor celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer 42:2751–2756. doi:10.1016/j.ejca.2006.08.014 PubMedCrossRef

16.

Greene FL PD, Fleming ID (2002) AJCC Cancer Staging Manual. Springer, New York

17.

Hyun CL, Lee HE, Kim KS, Kim SW, Kim JH, Choe G, Park SY (2008) The effect of chromosome 17 polysomy on HER-2/neu status in breast cancer. J Clin Pathol 61:317–321. doi:10.1136/jcp.2007.050336 PubMedCrossRef

18.

Park JY, Cho MO, Leonard S, Calder B, Mian IS, Kim WH, Wijnhoven S, van Steeg H, Mitchell J, van der Horst GT, Hoeijmakers J, Cohen P, Vijg J, Suh Y (2008) Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice. PLoS One 3:e2346. doi:10.1371/journal.pone.0002346 PubMedCrossRef

19.

De Santis G, Miotti S, Mazzi M, Canevari S, Tomassetti A (2009) E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K–p85 regulatory subunit to adherens junctions of ovarian carcinoma cells. Oncogene 28:1206–1217. doi:10.1038/onc.2008.470 PubMedCrossRef

20.

Marinari B, Moretti F, Botti E, Giustizieri ML, Descargues P, Giunta A, Stolfi C, Ballaro C, Papoutsaki M, Alema S, Monteleone G, Chimenti S, Karin M, Costanzo A (2008) The tumor suppressor activity of IKKalpha in stratified epithelia is exerted in part via the TGF-beta antiproliferative pathway. Proc Natl Acad Sci USA 105:17091–17096. doi:10.1073/pnas.0809288105 PubMedCrossRef

21.

van Nes JG, de Kruijf EM, Faratian D, van de Velde CJ, Putter H, Falconer C, Smit VT, Kay C, van de Vijver MJ, Kuppen PJ, Bartlett JM (2011) COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients. Breast Cancer Res Treat 125(3):671–685PubMedCrossRef

22.

Kostopoulos I, Arapantoni-Dadioti P, Gogas H, Papadopoulos S, Malamou-Mitsi V, Scopa CD, Markaki S, Karagianni E, Kyriakou V, Margariti A, Kyrkou E, Pavlakis K, Zaramboukas T, Skordalaki A, Bourli A, Markopoulos C, Pectasides D, Dimopoulos MA, Skarlos D, Fountzilas G (2006) Evaluation of the prognostic value of HER-2 and VEGF in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy. Breast Cancer Res Treat 96:251–261. doi:10.1007/s10549-005-9062-2 PubMedCrossRef

23.

Spizzo G, Gastl G, Wolf D, Gunsilius E, Steurer M, Fong D, Amberger A, Margreiter R, Obrist P (2003) Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival. Br J Cancer 88:574–578. doi:10.1038/sj.bjc.6600741 PubMedCrossRef

24.

Lucci A, Krishnamurthy S, Singh B, Bedrosian I, Meric-Bernstam F, Reuben J, Broglio K, Mosalpuria K, Lodhi A, Vincent L, Cristofanilli M (2009) Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow. Breast Cancer Res Treat 117:61–68. doi:10.1007/s10549-008-0135-x PubMedCrossRef

25.

Haffty B, Yang Q, Moran M, Tan A, Reiss M (2008) Estrogen-dependent prognostic significance of cyclooxygenase-2 expression in early-stage invasive breast cancers treated with breast-conserving surgery and radiation. Int J Radiat Oncol Biol Phys 71:1006–1013. doi:10.1016/j.ijrobp.2007.11.063 PubMedCrossRef

26.

Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27:1168–1176. doi:10.1200/JCO.2008.18.1024 PubMedCrossRef

27.

Singh-Ranger G, Salhab M, Mokbel K (2008) The role of cyclooxygenase-2 in breast cancer: review. Breast Cancer Res Treat 109:189–198. doi:10.1007/s10549-007-9641-5 PubMedCrossRef

28.

Kelly LM, Hill AD, Kennedy S, Connolly EM, Ramanath R, Teh S, Dijkstra B, Purcell R, McDermott EW, O’Higgins N (2003) Lack of prognostic effect of Cox-2 expression in primary breast cancer on short-term follow-up. Eur J Surg Oncol 29:707–710. doi:10.1016/j.ejso.2003.07.001 PubMedCrossRef

29.

Boland GP, Butt IS, Prasad R, Knox WF, Bundred NJ (2004) COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br J Cancer 90:423–429. doi:10.1038/sj.bjc.6601534 PubMedCrossRef

30.

Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G (2006) Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer 43:163–168PubMedCrossRef

31.

Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66:5504–5511. doi:10.1158/0008-5472.CAN-05-4076 PubMedCrossRef

32.

Schmitz KJ, Callies R, Wohlschlaeger J, Kimmig R, Otterbach F, Bohr J, Lee HS, Takeda A, Schmid KW, Baba HA (2006) Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with Her-2/neu signalling pathways. J Clin Pathol 59:685–691. doi:10.1136/jcp.2005.030650 PubMedCrossRef

33.

Witton CJ, Hawe SJ, Cooke TG, Bartlett JM (2004) Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology 45:47–54. doi:10.1111/j.1365-2559.2004.01898.x PubMedCrossRef

Titel: COX2 overexpression is a prognostic marker for Stage III breast cancer
verfasst von: Hee Sung Kim
Hyeong-Gon Moon
Wonshik Han
Cha Kyung Yom
Woo Ho Kim
Jun Ho Kim
Dong-Young Noh
Publikationsdatum: 01.02.2012
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2012
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1521-3

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

COX2 overexpression is a prognostic marker for Stage III breast cancer

Abstract

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2012

Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression of the estrogen receptor by microRNAs

Evaluating breast cancer risk projections for Hispanic women

Is knowledge translation adequate? A quality assurance study of staging investigations in early stage breast cancer patients

Twenty-five year results of the national cancer institute randomized breast conservation trial

Prognostic value of acquired uniparental disomy (aUPD) in primary breast cancer

Correlation of white female breast cancer incidence trends with nitrogen dioxide emission levels and motor vehicle density patterns

Neu im Fachgebiet Onkologie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

Update Onkologie