Cytoplasmic PPARγ 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 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.

Combined COX-2/PPARγ Expression as Independent Negative Prognosticator for Vulvar Cancer Patients

“…These findings would explain the opposite effect on survival when PPARγ is detected in the nucleus or in the cytoplasm: Nuclear expressed PPARγ is a prognostically favorable factor in overall survival, but detection in the cytoplasm is a prognostically unfavorable factor in disease-free survival and shows an unfavorable trend in overall survival. Shao et al [ 94 ] described an unfavorable overall survival in breast cancer patients showing a high-expression level of PPARγ in cytoplasma. In some tumor entities, a positive prognostic influence of nuclear PPARγ expression on the survival of tumor patients has already been identified, but a difference between expression localization and relation to different patient outcome was not described [ 95 , 96 ].…”

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

“…Also in patients with breast and prostate cancer, PPARγ is a marker of better prognosis and is associated with better survival (161)(162)(163). Importantly, one study reports that cytoplasmic PPARγ expression appeared as an independent marker of poor prognosis in primary breast cancers (198). TCGA analysis proposed PPARγ as a favorable prognostic marker for renal and urothelial cancers ( Table 1).…”

PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy

“…prognostically unfavorable factor in disease-free and OS in various carcinoma, including in breast cancer [46,47]. These results indicate that the functional form of PPARγ may exert a potential protective role in breast cancer patients.…”

“…However, the prognostic significance of PPARγ in breast cancer is clearly different depending on its subcellular localization. Recent data have shown that nuclear expression of PPARγ is associated with longer OS, whereas detection in the cytoplasm is a prognostically unfavorable factor in disease-free and OS in various carcinoma, including in breast cancer [ 46 , 47 ]. These results indicate that the functional form of PPARγ may exert a potential protective role in breast cancer patients.…”