Elevated expression of cyclooxygenase‐2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma

Denkert, Carsten; Winzer, Klaus‐Jürgen; Müller, Berit-Maria; Weichert, Wilko; Pest, Sören; Köbel, Martin; Kristiansen, Glen; Reles, Angela; Siegert, Antje; Guski, H; Hauptmann, Steffen

doi:10.1002/cncr.11437

Cited by 218 publications

(194 citation statements)

References 26 publications

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“…In fact, our findings were obtained by analysis of a relatively large number of consecutively resected cases in a single institution and, thus, should be of considerable interest. Moreover, the monoclonal antibodies we used have been shown in several excellent studies (13,14,30,31,38) and is considered to give the most sensitive, specific, and reproducible immunoreactivity of Cox-2 protein. Nevertheless, as proposed by Buecher et al (28), it will be of critical importance to standardize the methods used for the evaluation of tumor Cox-2 status and to apply common interpretative criteria to allow direct comparison of results between laboratories.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 Expression

Soumaoro

Uetake

Higuchi

et al. 2004

Clinical Cancer Research

230

172

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Purpose: Recent studies have shown that cyclooxygenase (Cox)-2 may be involved in colorectal carcinogenesis. We aimed to determine whether Cox-2 expression in itself can predict outcome of colorectal cancer patient after surgery. In addition, the expression of Cox-1 was also evaluated.Experimental Design: Tissue samples of primary and secondary tumors from 288 patients undergoing surgical resections for colorectal adenocarcinoma were immunohistochemically examined for Cox-2 and Cox-1 expressions. The specimens were graded based on the intensity and extent of staining; then, the correlations between Cox-2 and Cox-1 expressions with clinicopathologic parameters and survival time were analyzed.Results: Expression of Cox-2 was positive in 70.8% of primary tumor, 92.0% of lymph node metastases, 100.0% of hepatic metastases, and was significantly associated with tumor size, depth of invasion, lymph node metastasis, vessels invasion, stage and recurrence. In contrast, Cox-1 was positive in 42.7% of primary tumor, 84.0% of lymph node metastases, 37.5% hepatic metastases, and was associated with only tumor size. Patients with Cox-2-positive tumors had a significant shorter survival time than those with negative tumors did (P ‫؍‬ 0.0006 by log-rank test); and, in a multivariate analysis, Cox-2 was an independent prognostic factor (P ‫؍‬ 0.0103; relative risk 4.114; 95% confidence interval, 1.397-12.120). Cox-1 status had no statistically effect on patient survival time.Conclusions: Elevated Cox-2 expression, but not that of Cox-1, was significantly associated with reduced survival and recognized as an independent prognostic factor in our cohort of colorectal cancer patients.

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase-2 Expression

Soumaoro

Uetake

Higuchi

et al. 2004

Clinical Cancer Research

230

172

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“…Final scores of more than 6 were regarded as positive expression. 8,19 Expression of COX-2 in endothelial cells was also recorded.…”

Section: Immunohistochemical Staining For Cox-2mentioning

confidence: 99%

Prostanoid receptor EP1 expression in breast cancer

et al. 2008

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Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P ¼ 0.032) and inversely with node positivity (P ¼ 0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P ¼ 0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression. Keywords: breast cancer; EP1 receptor; cyclooxygenase; PGE2; prostanoid receptor; immunohistochemistry Breast cancer is one of the most common malignancies in developed countries including USA, and the second leading cause of cancer-related deaths in women. 1 As the incidence of breast cancer is increasing, several attempts at testing various preventive agents have been made (reviewed by Arun and Hortobagyi 2 ). Nonsteroidal anti-inflammatory drugs (NSAIDs), which act through inhibition of cyclooxygenase enzyme (COX), are one such class of drugs that have been studied for their possible role in breast cancer prevention. Epidemiological studies investigating the relationship between NSAID use and breast cancer have reported conflicting results; some studies 3-5 show 30-40% reduction in breast cancer incidence with NSAID use, whereas others failed to confirm this relationship. 6,7 NSAIDs work by inhibiting both constitutive and inducible cyclooxygenase enzymes (COX-1 and COX-2, respectively), both of which have been postulated to play a role in carcinogenesis. Elevated cyclooxygenase-2 (COX-2) expression is a marker of poor prognosis in human breast cancer and correla...

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“…Over 40% of human breast tumors have been found to have high expression of the cyclooxygenase-2 (COX-2) protein [2][3][4]. High COX-2 expression in breast tumors has been correlated with poor survival, distant metastasis and lower local-regional control of disease [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…High COX-2 expression in breast tumors has been correlated with poor survival, distant metastasis and lower local-regional control of disease [2,3]. Ectopic expression of COX-2 in breast cancer cell lines was found to increase the production of prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8), which are essential to COX-2-induced breast cancer invasion [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

Nieves-Alicea

Colburn

Simeone

et al. 2008

Breast Cancer Res Treat

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High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE 2 and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE 2 and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE 2 and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE 2 and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE 2 and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE 2 and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.

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Elevated expression of cyclooxygenase‐2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma

Cited by 218 publications

References 26 publications

Cyclooxygenase-2 Expression

Cyclooxygenase-2 Expression

Prostanoid receptor EP1 expression in breast cancer

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

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