Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study

Abstract

Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy. We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study. Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival ( = 160; HR, 0.56; = 0.03) and 5-year overall survival (HR, 0.53; = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology. The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer. TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. .

TLE2 is associated with favorable prognosis and regulates cell growth and gemcitabine sensitivity in pancreatic cancer

“…TLE proteins have been observed to interact with transcriptional factors, including Hes, c-Myc, and Runx (12,13). Additionally, some studies have reported that TLE1 and TLE3 can participate in tumor development as tumor suppressor genes (14)(15)(16)(17).…”

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation

“…In AML cell lines, loss of TLE4 and Wnt signaling pathway activation increased the expression of proinflammatory genes and induced resistance to chemotherapy (Shin et al, 2016). In studies of ovarian and breast cancers, increased TLE3 expression was related to a higher response rate to taxane-based chemotherapy, but TLE3 expression showed no predictive value in treating breast cancer at an early stage (Samimi et al, 2012;Ring et al, 2018). The level of TLE3 expression was also found to be positively correlated with the sensitivity of breast cancer cells to tamoxifen treatment (van Agthoven et al, 2009).…”

“…Further evidence from recent studies showed that genetic deletion of TLE genes in mice could cause significant defects, especially in the hematopoietic, neuronal, and musculoskeletal systems (Gasperowicz et al, 2013;Wheat et al, 2014;Ramasamy et al, 2016). Moreover, TLEs are abnormally expressed in various tumors and are involved in tumorigenesis (Dayyani et al, 2008;Holmes et al, 2012;Okada et al, 2017;Ring et al, 2018;Palit et al, 2019;Wang et al, 2020). TLEs also regulate the development of progenitor immune cells, and their function in mature immune cells is increasingly being recognized (Wheat et al, 2014;Ramasamy et al, 2016;Xing et al, 2018;Zhang et al, 2019).…”