Reduced Expression of Cyclooxygenase-2 in Primary Breast Cancer

Journal of the National Cancer Institute (Impact Factor: 12.58). 08/2008; 100(14):1042-3. DOI: 10.1093/jnci/djn194
Source: PubMed

ABSTRACT Recently reported results of a phase 2 study combining the aromatase inactivator exemestane with the cyclooxygenase-2 (COX-2) inhibitor celecoxib for the treatment of breast cancer showed that patients receiving the combined treatment had response rates and clinical benefit rates that were similar to those of the group receiving exemestane only (1). The rationale for using a COX-2 inhibitor for the treatment of breast cancer is based on several reports that COX-2 is frequently overexpressed in breast cancer (2) and that elevated levels of COX-2 in breast cancer specimens were associated with tumor progression and poor prognosis (3). The disappointing effect of celecoxib in this clinical study indicates that COX-2 may not be as crucial for the progression of human breast cancer as previously hypothesized. A possible explanation for the unexpected findings could be that the reported overexpression of COX-2 in …

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Available from: Daniel F Legler, Jul 28, 2015
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    • "Cox-2 is expressed in human breast tumours and has been found in both early-stage atypical hyperplasias and invasive cancers [38]. However, recent studies have suggested that in contrast to previous studies, Cox-2 expression is decreased in invasive breast cancers [34,39,40]. Therefore, although the use of Cox-2 inhibitors in late-stage breast cancer may be limited, epidemiological studies suggest that Cox-2 inhibition may be relevant for breast cancer prevention. "
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    ABSTRACT: Inflammation within the tumour microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. We have previously demonstrated that activation of a mouse mammary tumour virus (MMTV)-driven inducible fibroblast growth factor receptor 1 (iFGFR1) transgene in mammary epithelial cells results in an inflammatory response characterised by induction of inflammatory genes in the mammary gland. Specifically, we have observed increased levels of IL-1beta expression in the mammary gland following activation of iFGFR1 and have used the iFGFR1 model to elucidate the function of IL-1beta in promoting iFGFR1-induced mammary lesions. To determine the functional consequences of IL-1beta induction during FGFR1-induced mammary tumourigenesis, the effects of IL-1beta inhibition on the formation of epithelial hyperplasias were examined using the MMTV-iFGFR1 transgenic mouse model. Further studies used a combination of the HC-11 mammary epithelial cell line that stably expresses iFGFR1 and the MMTV-iFGFR1 transgenic mice to further define the mechanisms of IL-1beta function. Inhibition of IL-1beta activity in vivo resulted in reduced iFGFR1-induced epithelial proliferation and formation of hyperplastic structures. Further studies demonstrated that treatment of mammary epithelial cells with IL-1beta-induced expression of cyclooxygenase (Cox)-2 both in vitro and in vivo. Finally, inhibition of Cox-2 prior to activation of iFGFR1 in the transgenic mice also resulted in decreased iFGFR1-induced formation of hyperplastic structures. The results from these studies indicate that targeting the inflammatory cytokine IL-1beta partially inhibits iFGFR1-induced formation of early-stage mammary lesions, in part through induction of Cox-2. These findings demonstrate that activation of a growth factor receptor in mammary epithelial cells results in increased expression of inflammatory mediators, which cooperate to promote the initiation of hyperplastic lesions in the mammary gland.
    Breast cancer research: BCR 05/2009; 11(2):R21. DOI:10.1186/bcr2246 · 5.49 Impact Factor
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    ABSTRACT: Aromatase inhibitors (AIs) are well established in the treatment of metastatic hormone-sensitive breast cancer in postmenopausal women. Cyclooxygenase (COX)-2 inhibitors have demonstrated efficacy in reducing cancer risk in animal and human studies. In several preclinical studies, combination AI plus COX-2 inhibitor therapy has shown a synergistic antitumor effect. This review describes the utility of AI plus COX-2 inhibitor therapy and discusses the completed and ongoing clinical trials investigating treatment with the AI exemestane and the COX-2 inhibitor celecoxib in the neo-adjuvant and metastatic breast cancer settings. In general, combination therapy had comparable or better efficacy compared with AI monotherapy using the end points of progression-free survival, overall response rate, clinical benefit rate, time to progression, and duration of clinical benefit. All therapies were well tolerated. There appeared to be a beneficial impact on serum lipid levels for patients receiving combination therapy in a neo-adjuvant trial despite the known cardiovascular toxicity risk associated with COX-2 inhibitors. In conclusion, AIs plus COX-2 inhibitors have shown promising efficacy and safety for the treatment of patients with metastatic breast cancer. Careful monitoring during future trials will be necessary to accurately assess the risk-benefit ratio of combination therapy.
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    ABSTRACT: Prostaglandin E(2) (PGE(2)) is the most abundant eicosanoid and a very potent lipid mediator. PGE(2) is produced predominantly from arachidonic acid by its tightly regulated cyclooxygenases (COX) and prostaglandin E synthases (PGES). Secreted PGE(2) acts in an autocrine or paracrine manner through its four cognate G protein coupled receptors EP1 to EP4. Under physiological conditions, PGE(2) is key in many biological functions, such as regulation of immune responses, blood pressure, gastrointestinal integrity, and fertility. Deregulated PGE(2) synthesis or degradation is associated with severe pathological conditions like chronic inflammation, Alzheimer's disease, or tumorigenesis. Therefore, pharmacological inhibition of COX enzymes and PGE(2) receptor antagonism is of great therapeutic interest.
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