Role of TRAP1 and estrogen receptor alpha in patients with ovarian cancer -A study of the OVCAD consortium

Abstract

BackgroundThe role of the tumor necrosis factor receptor associated protein 1 (TRAP1) – supposed to be involved in protection of cells from apoptosis and oxidative stress – has just started to be investigated in ovarian cancer. TRAP1 has been shown to be estrogen up-regulated in estrogen receptor α (ERα) positive ovarian cancer cells. The clinical impact of TRAP1 is not clear so far and the significance of ERα expression as therapeutic and prognostic marker is still controversial. Therefore, we investigated the importance of TRAP1 together with ERα in regard to clinicopathological parameters, chemotherapy response, and survival.Methods and resultsExpressions of TRAP1 and ERα were evaluated by immunohistochemical staining of tissue microarrays comprised of 208 ovarian cancer samples. TRAP1 was highly expressed in 55% and ERα was expressed in 52% of all cases. High TRAP1 expression correlated significantly with ERα (p < 0.001) but high TRAP1 expression was also found in 42% of ERα negative cases. High TRAP1 expression correlated significantly with favorable chemotherapy-response (HR = 0.48; 95%CI 0.24-0.96, p=0.037) and showed a significant impact on overall survival (OS) (HR = 0.65; 95%CI 0.43-0.99, p = 0.044). ERα expression was a favorable prognostic factor for OS in univariate and multivariate analyses. Interestingly, the combined pattern (ERα positive and/or TRAP1-high) revealed the strongest independent and significant positive influence on OS (HR = 0.41; 95%CI 0.27-0.64).ConclusionImmunohistochemical evaluation of TRAP1 together with ERα provides significant prognostic information. TRAP1 alone is significantly associated with chemotherapy response and overall survival, rendering TRAP1 as interesting scientific and therapeutic target.

TRAP1 Shows Clinical Significance and Promotes Cellular Migration and Invasion through STAT3/MMP2 Pathway in Human Esophageal Squamous Cell Cancer

“…Furthermore, TRAP1 has been associated with chemoresistance, as it blocks the drug-induced apoptosis in prostate cancer, colorectal cancer, breast cancer, and ovarian carcinoma (Costantino et al, 2009;Leav et al, 2010;Aust et al, 2012;Maddalena et al, 2013). In the present study, we also observed that upregulation of TRAP1 antagonized cisplatin-induced apoptosis, while downregulation of TRAP1 sensitized the cells to cisplatin.…”

TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial–mesenchymal transition

“…18 In fact, TRAP1 has an important role in the progression from a localized to a metastatic disease 19 and lower TRAP1 levels correlated with increased overall survival 20 in colorectal cancers, whereas high TRAP1 expression correlates significantly with favorable chemotherapy response and longer overall survival in OC. 21 Consistently, we have recently shown that TRAP1 expression inversely correlates with grade and stage and directly correlates with survival in a large cohort of OC patients, and that low TRAP1 in OC cells and tissues associated with a metabolic shift, ultimately causing the onset of resistance to cisplatin-based chemotherapy. 22 Herein, we show that TRAP1 is often deleted in high-grade serous OC and that TRAP1 expression is correlated with the copy number.…”

Estrogen Biosynthesis and Action in Ovarian Cancer

“…However, in other studies, high expression of ER-α was found to be associated with a better prognosis (111, 112). Also higher ER-β levels were significantly associated with longer disease-free survival and a longer overall survival in one study.…”