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

ABSTRACT: BACKGROUND:The aim of this study was to investigate the expression of the nuclear receptor PPAR?, 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, PPAR?, 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:PPAR? was expressed in almost 58% of the samples with a predominant cytoplasmic location. Cox-1 and Cox-2 were exclusively cytoplasmic. Cytoplasmic PPAR? was inversely correlated with nuclear PPAR? 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 PPAR? 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 PPAR? expression appeared as an independent marker of poor prognosis. In support of this cross-talk between PPAR? and Cox-1, we found that Cox-1 became a marker of good prognosis only when cytoplasmic PPAR? was expressed at high levels. CONCLUSION:Altogether, these data suggest that the relative expression of cytoplasmic PPAR? 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.

SUBMITTER: Shao W

PROVIDER: S-EPMC7035771 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Shao Wanting W Kuhn Christina C Mayr Doris D Ditsch Nina N Kailuwait Magdalena M Wolf Verena V Harbeck Nadia N Mahner Sven S Jeschke Udo U Cavaillès Vincent V Sixou Sophie S

Journal of translational medicine 20200221 1

<h4>Background</h4>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.<h4>Methods</h4>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 aggr ...[more]

PMID: 32085795

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Project description:PurposeEmerging data suggest immune checkpoint inhibitors have reduced efficacy in heavily pretreated triple-negative breast cancers (TNBC), but underlying mechanisms are poorly understood. To better understand the phenotypic evolution of TNBCs, we studied the genomic and transcriptomic profiles of paired tumors from patients with TNBC.Experimental designWe collected paired primary and metastatic TNBC specimens from 43 patients and performed targeted exome sequencing and whole-transcriptome sequencing. From these efforts, we ascertained somatic mutation profiles, tumor mutational burden (TMB), TNBC molecular subtypes, and immune-related gene expression patterns. Stromal tumor-infiltrating lymphocytes (stromal TIL), recurrence-free survival, and overall survival were also analyzed.ResultsWe observed a typical TNBC mutational landscape with minimal shifts in copy number or TMB over time. However, there were notable TNBC molecular subtype shifts, including increases in the Lehmann/Pietenpol-defined basal-like 1 (BL1, 11.4%-22.6%) and mesenchymal (M, 11.4%-22.6%) phenotypes, and a decrease in the immunomodulatory phenotype (IM, 31.4%-3.2%). The Burstein-defined basal-like immune-activated phenotype was also decreased (BLIA, 42.2%-17.2%). Among downregulated genes from metastases, we saw enrichment of immune-related Kyoto Encyclopedia of Genes and Genomes pathways and gene ontology (GO) terms, and decreased expression of immunomodulatory gene signatures (P < 0.03) and percent stromal TILs (P = 0.03). There was no clear association between stromal TILs and survival.ConclusionsWe observed few mutational shifts, but largely consistent transcriptomic shifts in longitudinally paired TNBCs. Transcriptomic and IHC analyses revealed significantly reduced immune-activating gene expression signatures and TILs in recurrent TNBCs. These data may explain the observed lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to better understand these initial observations.See related commentary by Savas and Loi, p. 526.

Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P?=?0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P?=?0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P?=?0.003 in LN+ cases; P?=?0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P?=?0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P?=?0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

Dataset Information

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

Publications

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

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