Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E2 and 15‐deoxy‐Δ12,14‐prostaglandin J2 in human breast cancer and metastasis

Badawi, Alaa; Badr, Mostafa Z.

doi:10.1002/ijc.10770

Cited by 54 publications

(59 citation statements)

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“…3). Taken together the studies of Badawi and Badr, the current study and those previous reported, 25 it is clear that there is a stepwise decrease of PPAR␥ from normal healthy breast tissues, 38 tumor unaffected breast tissue, primary tumor tissues to metastatic tumor tissues. This reduction is linked to the prognosis of the patients with breast cancer.…”

Section: Reduced Level Of Pgc-1 In Patients Who Have a Poor Prognosissupporting

confidence: 86%

“…Although PGC-1 exhibited similar levels in tumor and normal tissues, the reduction of the co-activator, similar to that of PPAR␥, has clearly occurred in tumors with aggressive nature, i.e., in TNM3 and TNM4 tumors and tumors from patients with a poor prognosis. Badawi and Badr 38 have reported recently that unaffected background normal tissues exhibited lower levels of PPAR␥ than normal breast tissues from non-tumor bearing patients and that metastatic tumors had lower levels of PPAR␥ than the primary tumors. 38 Although the study by Badawi and Badr did not provide information on relationship between PPAR␥ and clinical outcomes, the current study has provided data to show that over a period 6-year follow-up , the levels of PPAR␥ in patients with local recurrence and those who died of breast cancer were significantly lower than those who remained disease free (Fig.…”

Section: Reduced Level Of Pgc-1 In Patients Who Have a Poor Prognosismentioning

confidence: 99%

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Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes

Jiang

Douglas-Jones

Mansel

2003

Intl Journal of Cancer

153

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Peroxisome-proliferator activated receptor-gamma (PPAR␥) belongs to a family of nuclear receptors and acts as receptor for peroxisome-proliferators, steroids, retinoic acids, and polyunsaturated fatty acids. Our study examined the transcript levels of peroxisome-proliferator activated receptorgamma (PPAR␥) and its co-activator (PGC-1) in a cohort of patients with breast cancer. An invasive breast cancer cell, MDA MB 231 exhibited lower level of expression of PPAR␥, compared to non-invasive MCF-7. Breast cancer tissues (n ‫؍‬ 120) exhibited a lower level of PPAR␥ mRNA compared to normal tissues (n ‫؍‬ 25, p ‫؍‬ 0.05). No difference, however, was seen with PGC-1. Although the levels of PPAR␥ and PGC-1 did not correlate with nodal involvement and grade, significantly lower levels of PPAR␥ were seen in TNM3 and TNM4 tumors and from patients with local recurrence and those who died of breast cancer. Lowest level of PGC-1 was also seen in TNM3 and TNM4 tumors and patients who died of breast cancer. We conclude that there is aberrant expression of PPAR␥ and its co-activator, PGC-1, in human breast cancer and low levels of these molecules in cancer tissues are associated with poor clinical outcomes. Peroxisome proliferator activator receptor-gamma (PPAR␥) belongs to a nuclear hormone receptor superfamily that regulates gene expression. 1-3 PPAR␥ contain DNA, lipid and A/B binding domains that recognize DNA response elements in the promoters of their target genes and interact with lipid ligands 4 and prostaglandins (PG J2). 5,6 Ligands for PPAR␥ such as troglitazone, BRL 49653, 15S-hydroxyeicosatetraenoic acid , and 15-deoxy-Delta 12,14-prostaglandin J2 have been shown to inhibit the growth of tumors and induce apoptosis of cancer cells, 7-10 and inhibit colon tumorigenesis in animal models. 11-14 PPAR␥ forms a complex with the PPAR␥ coactivators (PGC-1 and PGC-2) 21,22 and, together with other transcription factors SRC-1 and the CREB binding protein, 23 regulates gene expression, including cyclin regulator p27kip1, cMET protooncogene, and E-cadherin. The inhibition of cell growth by PPAR␥ agonists appears to be via multiple ways, including the inhibition of cyclin D1 15 and increase the level of cell cycle inhibitor P27 kip1 . 16 The proliferation of cancer cells that express PPAR␥ can be inhibited by its ligands and, interestingly, that the effect can be further enhanced by 9-cis retinoic acid, a ligand of RXR alpha. 17 PPAR␥ agonists can also reduce the growth and progressive activities of prostate cancer cells 18,19 and inhibit transcription of genes that are involved in tumor progression, such as the HGF receptor, cMET. 20 Abnormalities in PPAR family members have been implicated in tumorigenesis in animal models and in human cancers. PPAR␣ has been shown to be overexpressed in human prostate cancer. 24,25 Mutation of PPAR␥ has also been reported on colorectal cancer. PPAR␥ can be upregulated by agents such as butyrate in cancer cells. 26 We and others have shown that polyunsaturated fatty acids, such as gamma linol...

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Section: Reduced Level Of Pgc-1 In Patients Who Have a Poor Prognosissupporting

confidence: 86%

Section: Reduced Level Of Pgc-1 In Patients Who Have a Poor Prognosismentioning

confidence: 99%

Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes

Jiang

Douglas-Jones

Mansel

2003

Intl Journal of Cancer

153

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“…[37][38][39][40] Our results show that HLD downregulates the level of PPARc mRNA. Underexpression of PPARc in rodent and human mammary gland carcinomas 41,42 and in human prostate adenocarcinomas have been reported previously. 43 Moreover, Sarraf et al 44 detected somatic loss-of-function mutations in the gene encoding PPARc in a few cases of sporadic colorectal carcinoma, suggesting that the wild-type gene compromises the survival of abnormal cells.…”

Section: Discussionsupporting

confidence: 65%

A high‐fat diet generates alterations in nuclear receptor expression: Prevention by vitamin A and links with cyclooxygenase‐2 and β‐catenin

Delage¹,

Bairras²,

Buaud³

et al. 2005

Intl Journal of Cancer

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Epidemiologic studies suggest that intake of high energy from fat, inducing overweight, increases the risk of cancer development and promotes colon carcinogenesis. It is therefore important to understand which parameters are affected early on by a high-fat diet in order to devise and improve protective nutritional strategies. We investigated the effect of high energy/fat intake on colon mucosa of male Wistar rats induced by a single 1,2-dimethylhydrazine (DMH) injection. Aberrant crypt foci (ACF) were numbered and modifications in cyclooxygenase-2 (COX-2) and b-catenin levels assessed. Peroxisome proliferator-and retinoic acid-activated receptors (PPAR and RAR, RXR) are key transcription factors regulating gene expression in response to nutrient-activated signals. A short-term study was designed to evaluate whether alterations in mRNA expression of nuclear receptors can be detected at the beginning of the weight gain phase induced by an appetizing hyperlipidic diet (HLD). HLD consumption induced early downregulation of PPARc (-33.1%) and RARb (-53.1%) mRNA expression concomitant with an increase in levels of COX-2 (145.5%) and b-catenin (184.56%) and in the number of ACF (191.56 6 88.60 vs. 21.14 6 11.64, p < 0.05). These findings suggest that HLD increases ACF occurrence, possibly through alterations in the mRNA expression profile of nuclear receptors. Moreover, the use HLD rich in retinyl esters or supplemented with all-trans retinoic acid led to a reduction in the number of ACF. Vitamin A also prevented HLD-induced alterations and the increase in levels of COX-2 and b-catenin. The present observations show a protective role for vitamin A against disturbances associated with HLD exposure in induced colon carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: colon carcinogenesis; nuclear receptor; high energy/fat intake; vitamin A The incidence of obesity and colon cancer is increasing in all industrialized countries. Colon carcinogenesis is a multifactorial disease, and diet is strongly involved in its etiology. A prospective cohort study has reported that increased body weight was associated with increased death rates form cancer.1 Thus, the high prevalence of obesity, explained by a lifestyle characterized by high energy/fat intake, led to increased risk of colon cancer development. These conclusions are reinforced by data suggesting that the number of preneoplastic colonic lesions 2-4 induced by a high-fat diet is reduced by restriction of energy intake 5 or by fiber-and vitamin-rich diets. 6,7 These data illustrate the potential of nutritional methods for reducing the deleterious consequences of high fat/energy intake on the risk of colon cancer.It is likely that diet affects cancer occurrence at the level of the cell signaling pathways rather than at the level of mutations. Nuclear receptors have a central role in the regulation of gene expression in response to diet. Thus, growing evidence points to the involvement of nuclear receptors in colon tumorigenesis. Indeed, they function as ligand-activated transcr...

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“…Thus it has been suggested that high expression of PPARg and low expression of COX-2 in the tumours might be involved in attenuating the capacity of the tumours to develop more malignant nature. Badawi and Badr (2003) described that an increase of COX-2 expression and a decrease of PPARg expression in breast carcinoma tissues were paralleled by increases in the tissue levels of PGE 2 and decreases in 15d-PGJ 2 and their altered expressions might influence the development of human breast carcinoma. COX-2 overexpression has been observed in many tumour types including gynaecological malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…Inoue et al (2000) proposed that expression of COX-2 was regulated by a negative feedback loop mediated through PPARg in macrophages. Badawi and Badr (2003) described that the altered expression of COX-2 and PPARg might influence the development of human breast carcinoma and its progression to metastasis. Recently, PPARg has been reported to be localised primarily to granulosa cells in ovarian tissue and to be involved in follicular development (Komar et al, 2001).…”

mentioning

confidence: 99%

Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor γ in epithelial ovarian tumours

et al. 2004

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Expression of cyclooxygenase (COX)-2 plays a key role in tumorigenesis and development and peroxisome proliferator-activated receptor g (PPARg) has been implicated in the control of COX-2 expression in some tissues. The aim of this study is to investigate (1) whether expression of COX-2 and PPARg is associated with ovarian carcinogenesis and progression of ovarian tumours and (2) whether COX-2 expression is controlled through ligand-mediated activation of PPARg in ovarian carcinoma cells. For this purpose, the presence of COX-2 and PPARg was immunohistochemically examined in 71 epithelial ovarian carcinomas, 18 borderline tumours and 23 benign tumours and the levels of COX-2 and PPARg proteins were determined by enzyme immunoassay in four benign tumours, three borderline tumours and 12 carcinomas. The frequency of COX-2 and PPARg detection was significantly increased and decreased as lesions progressed to carcinoma, respectively. The COX-2 protein was not detected in the three borderline tumours, whereas PPARg protein was detected in all of them. COX-2 protein was detected in eight of the 12 carcinomas, whereas PPARg protein was detected in only two cases. In addition, PPARg protein was not detected in all of the eight carcinomas in which COX-2 protein was detected, suggesting that expression of PPARg and COX-2 was in a reciprocal relationship. Furthermore, in cultured ovarian carcinoma cells, Western blot revealed that PPARg and COX-2 expression was regulated conversely as a result of stimulation by 15-deoxy-D 12, 14 PGJ 2 (15-PGJ 2 ), a PPARg activator. In addition, 15d-PGJ 2 suppressed tumour necrosis factor-ainduced-COX-2 expression, confirming the reciprocal correlation between COX-2 and PPARg. From these results, it was suggested that PPARg activation might suppress COX-2 expression via the nuclear factor-kB pathway in the ovarian carcinoma cells and that low expression of PPARg and high expression of COX-2 might be involved in carcinogenesis and progression of ovarian tumours.

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Expression of cyclooxygenase‐2 and peroxisome proliferator‐activated receptor‐γ and levels of prostaglandin E₂ and 15‐deoxy‐Δ^12,14‐prostaglandin J₂ in human breast cancer and metastasis

Cited by 54 publications

References 44 publications

Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes

Expression of peroxisome‐proliferator activated receptor‐gamma (PPARγ) and the PPARγ co‐activator, PGC‐1, in human breast cancer correlates with clinical outcomes

A high‐fat diet generates alterations in nuclear receptor expression: Prevention by vitamin A and links with cyclooxygenase‐2 and β‐catenin

Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor γ in epithelial ovarian tumours

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