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      Cytoplasmic PPARγ is a marker of poor prognosis in patients with Cox-1 negative primary breast cancers

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          Abstract

          Background

          The aim of this study was to investigate the expression of the nuclear receptor PPARγ, together with that of the cyclooxygenases Cox-1 and Cox-2, in breast cancer (BC) tissues and to correlate the data with several clinicobiological parameters including patient survival.

          Methods

          In a well characterized cohort of 308 primary BC, PPARγ, Cox-1 and Cox-2 cytoplasmic and nuclear expression were evaluated by immunohistochemistry. Correlations with clinicopathological and aggressiveness features were analyzed, as well as survival using Kaplan–Meier analysis.

          Results

          PPARγ was expressed in almost 58% of the samples with a predominant cytoplasmic location. Cox-1 and Cox-2 were exclusively cytoplasmic. Cytoplasmic PPARγ was inversely correlated with nuclear PPARγ and ER expression, but positively with Cox-1, Cox-2, and other high-risk markers of BC, e.g. HER2, CD133, and N-cadherin. Overall survival analysis demonstrated that cytoplasmic PPARγ had a strong correlation with poor survival in the whole cohort, and even stronger in the subgroup of patients with no Cox-1 expression where cytoplasmic PPARγ expression appeared as an independent marker of poor prognosis. In support of this cross-talk between PPARγ and Cox-1, we found that Cox-1 became a marker of good prognosis only when cytoplasmic PPARγ was expressed at high levels.

          Conclusion

          Altogether, these data suggest that the relative expression of cytoplasmic PPARγ and Cox-1 may play an important role in oncogenesis and could be defined as a potential prognosis marker to identify specific high risk BC subgroups.

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          Most cited references46

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          PPAR gamma gene--a review.

          Peroxisome proliferator-activated receptor gamma (PPARγ) has been the focus of intense research because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. There have been described three PPAR isotypes α, δ and γ which have an integrated role in controlling the expression of genes playing key roles in the storage and mobilization of lipids, in glucose metabolism, in morphogenesis and inflammatory response. Recent advances include the discovery of novel genes that are regulated by PPARγ, which helps to explain how activation of this adipocyte predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPARγ ligands, which promotes fatty acid storage in fat deposits and regulates the expression of adipocyte-secreted hormones that impacts on glucose homeostasis. So the net result of the pleiotropic effects of PPARγ ligands is improvement of insulin sensitivity. This review highlights the roles that PPAR gamma play in the regulation of gene expression of multiple diseases including obesity, diabetes and cancer and highlights the gene isolation transformation role. Further studies are needed for the transformation of PPAR gamma gene in plants and evaluate in animals for the treatment of type 2 diabetes.
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            COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

            The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-γ in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-γ in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.
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              Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer.

              Numerous studies have demonstrated that the levels of prostaglandins are greater in various cancers, including breast cancer and colon cancer, than in normal tissues. In particular, the inducible form of cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin biosynthesis, is overexpressed in colon tumors. Epidemiologic studies have demonstrated that the use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of colon cancer and, to a lesser extent, the risk of breast cancer. NSAIDs are known to inhibit COX, suggesting that the beneficial effect of NSAIDs in colon cancer may be related to COX overexpression in this disease. This possibility led us to ask whether COX is also overexpressed in breast cancers. Surgical specimens from 44 patients with breast cancer who had undergone lumpectomy or mastectomy were analyzed by immunoblot analysis and immunohistochemical analysis to determine the expression profile of the constitutively expressed form of cyclooxygenase (COX-1) and the inducible form (COX-2); the specimens from 14 patients included normal breast tissue. Expression of COX-1 protein was substantially higher in 30 of 44 tumor samples than in any of the 14 normal tissue specimens. Immunoblot analysis revealed extremely high levels of COX-2 protein in two tumor samples. Immunohistochemical staining of specimens that expressed COX-1 and/or COX-2 revealed that COX-1 was localized in stromal cells adjacent to the tumor but not in tumor cells. In contrast, COX-2 was localized primarily in tumor cells but also appeared in stromal cells. Our results suggest that overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial tumors.
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                Author and article information

                Contributors
                Wanting.Shao@med-uni-muenchen.de
                Christina.kuhn@med.uni-muenchen.de
                doris.mayr@med.uni-muenchen.de
                nina.ditsch@med.uni-muenchen.de
                magdalena.kailuweit@swmbrk.de
                verena-wolf@gmx.net
                nadia.harbeck@med.uni-muenchen.de
                sven.mahner@med.uni-muenchen.de
                udo.jeschke@med.uni-muenchen.de
                vincent.cavailles@inserm.fr
                sophie.sixou@inserm.fr
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                21 February 2020
                21 February 2020
                2020
                : 18
                : 94
                Affiliations
                [1 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Breast Center, Department of Obstetrics and Gynecology, University Hospital, , LMU Munich, ; Munich, Germany
                [2 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Pathology, , LMU Munich, ; Munich, Germany
                [3 ]GRID grid.121334.6, ISNI 0000 0001 2097 0141, IRCM-Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, , Université Montpellier, ; Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France
                [4 ]GRID grid.15781.3a, ISNI 0000 0001 0723 035X, Faculté des Sciences Pharmaceutiques, , Université Paul Sabatier Toulouse III, ; 31062 Toulouse Cedex 09, France
                [5 ]GRID grid.11417.32, ISNI 0000 0001 2353 1689, Cholesterol Metabolism and Therapeutic Innovations, Cancer Research Center of Toulouse (CRCT), UMR 1037, CNRS, Inserm, UPS, , Université de Toulouse, ; 31037 Toulouse, France
                Author information
                http://orcid.org/0000-0003-2623-3235
                Article
                2271
                10.1186/s12967-020-02271-6
                7035771
                32085795
                5b1c755e-d6ff-45e7-8ddb-346e58a14075
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 30 August 2019
                : 14 February 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004543, China Scholarship Council;
                Award ID: 201606170096
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Medicine
                pparγ,cytoplasmic,cox-1,cox-2,overall survival,breast cancer
                Medicine
                pparγ, cytoplasmic, cox-1, cox-2, overall survival, breast cancer

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