Harnessing the value of TCTP in breast cancer treatment resistance: an opportunity for personalized therapy

Abstract

Early identification of breast cancer (BC) patients at a high risk of progression may aid in therapeutic and prognostic aims. This is especially true for metastatic disease, which is responsible for most cancer-related deaths. Growing evidence indicates that the translationally controlled tumor protein (TCTP) may be a clinically relevant marker for identifying poorly differentiated aggressive BC tumors. TCTP is an intriguing protein with pleiotropic functions, which is involved in multiple signaling pathways. TCTP may also be involved in stress response, cell growth and proliferation-related processes, underlying its potential role in the initiation of metastatic growth. Thus, TCTP marks specific cancer cell sub-populations with pronounced stress adaptation, stem-like and immune-evasive properties. Therefore, we have shown that in vivo phospho-TCTP levels correlate with the response of BC cells to anti-HER2 agents. In this review, we discuss the clinical relevance of TCTP for personalized therapy, specific TCTP-targeting strategies, and currently available therapeutic agents. We propose TCTP as an actionable clinically relevant target that could potentially improve patient outcomes.

Keywords: Breast cancer; TCTP; biomarker; metastasis; stem cells; therapy resistance.

Figure 1

Genomic organization of TPT1. The UCSC genome browser was used to display the location and genomic organization of TPT1 on chromosome 13q14. Scheme of the TPT1 major types of alternative splicing is displayed (http://genome.ucsc.edu). UCSC Genome Browser on Human (GRCh38/hg38). TPT1: Tumor protein, translationally-controlled 1.

Figure 2

The peculiar structure of TCTP. (A) A cartoon representation of the secondary structure of human TCTP. Reference sequence from UniProt P13693^[11]. β-strands, α-helices and turns elements are indicated in the legend. The N-terminal region includes a flexible loop extending from β5 to β6 strands. It contains a highly conserved signature and the Ser46 and Ser64 residues which are phosphorylated by the polo-like kinase Plk1, a crucial player in mitosis. A second conserved signature is found in the C-terminal region; (B) The crystal structure of the human TCTP (PDB Code 1YZ1^[12]) discloses the α-helical hairpin (formed by Helix H2 and Helix H3), whose structure is similar to the H5-H6 helices of BCL-2 family proteins, and the β-stranded domain that shows a structural analogy with the guanine nucleotide exchange factors (GEF) Mss4/Dss4 protein families^[13], suggesting a similar role for TCTP as GEF for Ras homolog enriched in brain (Rheb) in the mTORC1 pathway^[14]. The flexible loop is not detectable in the crystal structure. TCTP: Translationally controlled tumor protein.

Figure 3

Correlation between Phospho-TCTP expression and response to trastuzumab therapy. Representative images of the immunohistochemical staining of phospho-TCTP in HER2 + BC patients (A) responsive and (B) non-responsive to trastuzumab. From Lucibello et al. “Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells”. Oncotarget, 2015 [Figure 6]^[19]. BC: Breast cancers; HER2: human epidermal growth factor receptor-2; TCTP: translationally controlled tumor protein.

Figure 4

TPT1/TCTP transcripts in BC and normal tissues. Boxplot from TPT1/TCTP RNAseq gene expression data of TCGA (upper panel) and METABRIC databases (Lower panel). (A) in normal tissue and primary breast cancer tissue; (B) in different PAM50 breast cancer subtypes; (C) in different stages of the tumor; (D) in metastatic (91 samples) vs. no metastatic tumors (59 samples); (E) in TP53 mutated tumors vs. TP53 wild-type tumors. BC: Breast cancers; MET: mesenchymal-epithelial transition; METABRIC: molecular taxonomy of breast cancer international consortium; TCGA: the cancer genome atlas; TCTP: translationally controlled tumor protein; TPT1: tumor protein, translationally-controlled 1.

Figure 5

High TCTP levels correlate with better clinical outcomes in BC patients. (A) TCGA survival curve (B) and Disease-Specific Survival in METABRIC dataset of BC patients separated according to TPT1 expression levels. BC: Breast cancers; BRCA: breast cancer susceptibility gene; METABRIC: molecular taxonomy of breast cancer international consortium; TCGA: the cancer genome atlas; TCTP: translationally controlled tumor protein; TPT1: tumor protein, translationally-controlled 1.

Figure 6

Overall survival is shorter in BC patients with higher TCTP expression. Kaplan-Meier analysis of overall survival in BC patients based on KM plotter database of: (A) PAM50 HER2 and (B) PAM50 basal subtypes. BC: Breast cancers; HER2: human epidermal growth factor receptor-2; TCTP: translationally controlled tumor protein; TPT1: tumor protein, translationally-controlled 1.

Figure 7

Overall survival is shorter in OC patients with higher TCTP expression. Kaplan-Meier analysis of overall survival in OC patients based on KM plotter dataset. OC: Ovarian cancer; TCTP: translationally controlled tumor protein; TPT1: tumor protein, translationally-controlled 1.

Figure 8

(A) Representative image of Artemisia Annua. https://commons.wikimedia.org/wiki/File:Artemisia_annua_-_001x.jpg. Created by: Oceancetaceen - Alice Chodura, Public domain, via Wikimedia; (B) Chemical structures of dihydroartemisinin. https://commons.wikimedia.org/wiki/File:Artenimol_(2).svg. Created by: Benff, CC BY-SA 4.0 <https://creativecommons.org.

Figure 9

Schematic overview of the potential application of TCTP in cancer. EVs: Extracellular vehicles; MDSCs: myeloid-derived suppressor cells; TCTP: translationally controlled tumor protein.

Figure 10

Pleiotropic functions of TCTP. A cartoon showing the major TCTP-related pathways. TCTP can promote cell proliferation by acting: (1) as a guanidine exchange factor for the GTP-binding protein Rheb, a crucial player in the mTORC1 pathway; (2) by inducing P53 degradation; (3) by regulating spindle morphology and mitosis progression, when it is phosphorylated by PLK1. TCTP can act as an immune-resistance factor via activation of TLR2 on myeloid cells, which in turn induces cytokines production and the recruitment of immune-suppressive cells. TCTP, in the phosphorylated form, can induce the activation of the EGFR/AKT pathway, thus promoting an immune resistance to anti-PD-L1 therapy. TCTP can promote cell migration and EMT markers through the mTORC2 pathways. EMT: Epithelial-mesenchymal transition; PD-L1: programmed death ligand-1; PLK1: polo-like kinase 1; TCTP: translationally controlled tumor protein.