Abstract
T-STAR (testis-signal transduction and activation of RNA) is an RNA binding protein, containing an SH3-binding domain and thus potentially playing a role in integration of cell signaling and RNA metabolism. The specific function of T-STAR is unknown and its implication in cancer is poorly characterized. Expression of T-STAR has been reported in human testis, muscle and brain tissues, and is associated with a growth-inhibitory role in immortalized fibroblasts. The aim of this paper was to investigate the functional role of T-STAR through (i) survival analysis of patients with primary invasive breast cancer and (ii) experimental evaluation of the effect of T-STAR on breast cancer cell growth. T-STAR protein expression was analysed by immunohistochemistry (IHC) in tissue microarrays with tumors from 289 patients with primary invasive breast cancer, and correlations to clinicopathological characteristics, recurrence-free and overall survival (RFS and OS) and established tumor markers such as HER2 and ER status were evaluated. In addition, the function of T-STAR was investigated using siRNA-mediated knock-down and overexpression of the gene in six breast cancer cell lines. Of the tumors analysed, 86% showed nuclear T-STAR expression, which was significantly associated with an improved RFS and strongly associated with positive HER2 status and negative hormone receptor status. Furthermore, experimental data showed that overexpression of T-STAR decreased cellular growth while knock-down increased it, as shown both by thymidine incorporation and metabolic activity. In summary, we demonstrate that T-STAR protein expression correlates with an improved RFS in primary breast cancer. This is supported by functional data, indicating that T-STAR regulation is of importance both for breast cancer biology and clinical outcome but future studies are needed to determine a potential role in patient stratification.
Highlights
Breast cancer is the most common cancer among women with 1.6 million new cases every year worldwide, and it is the type of cancer with the highest mortality, causing more than 400 000 deaths annually [1]
The dual localizations are in agreement with previous studies where the STAR family member QKI-5 has been found to be shuttled between the two compartments [32] and Sam68 is cytoplasmically expressed in various cancerous tissues [33,34,35]
Using a novel antibody reagent, IHC analysis revealed an association between the RNA-binding protein T-STAR and recurrence free survival (RFS) of patients afflicted by primary invasive breast cancer
Summary
Breast cancer is the most common cancer among women with 1.6 million new cases every year worldwide, and it is the type of cancer with the highest mortality, causing more than 400 000 deaths annually [1]. The clinical behavior is diverse and stratification is needed to subgroup patients that benefit from different treatment strategies, including HER2 targeted treatment [2]. It is clear that within subgroups, such as HER2 positive tumors, patients respond differently to selected therapy [8] and that further biological insight is needed. We have previously developed antibodies targeting tumorassociated antigens and screened them for differential binding to tumor and normal cells by immunohistochemistry (IHC) [9]. One of the antigens identified as being able to separate normal from malignant cells was the RNA-binding protein T-STAR (testissignal transduction and activation of RNA)
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