Skip to main content

Loss of Elf5 Wakes up “A Good Friend” of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Despite an aggressive approach in the management of TNBCs with current therapy, the recurrence and 5-year survival rates for TNBC stand at 50% and 37%, respectively. Therefore, for doctors and researchers, there is tense interest in finding new medications that can treat this kind of breast cancer more efficiently. 

E74-like transcription factor (Elf5) functions as a suppressor of epithelial-to-mesenchymal transition (EMT), a characteristic that imparts the tumor’s invasive and metastatic properties. Snahlata Singh et al. found that the loss of Elf5 increases tumor burden, growth and metastasis by activating intrinsic interferon- γ (IFN-γ), a cytokine that is both anti- and pro-tumorigenic. Mechanistically, they discovered that Elf5 inhibits IFN-γ signalling in TNBC tumor cells by upregulating the expression of Elf5-regulated ubiquitin ligase FBXW7, thereby promoting FBXW7-dependent IFN-γ receptor 1 (IFNGR1) ubiquitination and degradation (Figure1). They demonstrated that the absence of Elf5 led to reduced expression of FBXW7, increased production of IFNGR1 and activated IFN-γ signalling, which could potentially contribute to the increased invasive properties of TNBC tumor cells, followed by increased metastasis. In addition, enhanced expression of programmed death-ligand 1 (PD-L1) was observed, but Snahlata Singh et al. did not give a detailed explanation for this alternation. One possible illustration I can put forward here is that IFN-γ activates Jak-Stat pathway, which then induces the transcription of genes encoding PD-L1. Of course, more efforts and time should be devoted to testing this hypothesis further. 

Figure1. Low ELF5 and FBXW7 in TNBC tumor cells lead to stabilization of IFNGR1, resulting in increased PD-L1 expression. MDSC, myeloid-derived suppressor cell.

This study also provides new insight into immunotherapy. Due to the poor response rate of patients with TNBC receiving anti-PD-L1, the application of immune checkpoint blockades in TNBC patients is limited. However, for patients who are Elf5low and FBXW7low will express high levels of IFN- γ and PD-L1, making them susceptible to immunotherapeutic drugs. Obviously, this opens up the possibility to improve the clinical outcome for patients with TNBC by taking advantage of genetic and pharmacological approaches, together with antibodies targeting IFNGR1 and immune checkpoint inhibitors. 

References:
Snahlata Singh et al. Loss of ELF5–FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling.Nature Cell Biology, 22, 591-602 (May 2020)

Comments

Post a Comment

Popular posts from this blog

Lysine-Targeted Covalent Inhibitors Gaining Traction

In the past decade, targeted covalent inhibitors (TCIs) has experienced a resurgence due to its sustained target engagement and improved proteome-wide selectivity. Currently, targeting cysteine residues with acrylamides and other α, β-unsaturated carbonyl compounds is the predominant strategy in TCI development. Although lysine is more prevalent than cysteine and possesses lower mutation rates, lysine has been much less frequently considered and more challenging as a residue targeted by TCIs due to its low nucleophilicity. Recently, Jack Taunton and his colleagues reveled their two related work in JACS .   Based on the co-crystal structure of Hsp90 with a reversible inhibitor PU-H71, they designed two arylsulfonyl fluorides 1 and 2 and co-incubated them with Hsp90 protein (Figure 1a, b). Mass spectrometry detected the formation of a 1:1 covalent adduct. Mutation of Lys58 to arginine abrogated the covalent modification, indicating that the TCI selectively modified Lys58 (Fig...
Post a Comment
Read more

Multiple Postdoc and Technician Positions Available at Baylor College of Medicine

  Multiple postdoc and technician positions are available in Dr. Jin Wang’s group in the Department of Pharmacology and Chemical Biology at Baylor College of Medicine (BCM). BCM is located in the world largest medical center and has access to enormous biomedical resources. The research in the Wang lab is highly interdisciplinary and translational. The Wang lab has both chemistry and biology operations. For chemistry work, we have 17 chemical fume hoods, 4 ISCO combiflash chromatography systems, Agilent analytical LC-MS, Agilent preparative HPLC with auto-purification, and Genevac high throughput solvent evaporation, along with convenient access to 600 and 800 MHz NMR. For biology work, we have common equipment for biochemistry, molecular and cell biology, including tissue culture hoods, RT-PCR, plate reader, and imaging plate reader, and perform animal work to evaluate the efficacy of the experimental therapeutics developed in the group. In addition, we recently acquired a state-...
Post a Comment
Read more

RIPK2 PROTAC Burns up the Bridges between PK and PD

GlaxoSmithKline (GSK) previously reported a series of RIPK2 PROTACs with various E3 ligase binders (Figure 1). These PROTACs can degrade RIPK2 potently and efficiently in a concentration-dependent manner (Figure1). However, their poor solubility and high microsomal clearance limited their in vivo applications. To develop a RIPK2 degrader suitable for  in vivo  applications, the GSK group identified another IAP based RIPK2 PROTAC4 that is significantly different from PROTAC2, possessing a different RIPK2 binder, IAP ligase binder and linker (Figure2). PTROTAC4 can degrade RIPK2 in a time-dependent manner and shows reduced lipophilicity and lower clearance in hepatocytes. However, the modest binding affinity between the warhead of PROTAC4 and RIPK2 requires a high dose to reach efficient RIPK2 degradation. To address this limitation, the researchers performed extensive medicinal chemistry optimization based on PROTAC 4 and identified PROTAC 6 (Figure2), which contains an...
Post a Comment
Read more