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

Photoswitchable azopyrazoles Flipping the Switches of Ion Channels

Abnormally activated Ca 2+ channels are related to many human diseases, including Stormorken Syndrome, which makes Ca 2+ release-activated Ca 2+ (CRAC) channel a very promising therapeutic target. Several small molecule therapeutics targeting CRAC channels have been developed, including the GSKs series and Synta 66 . Those compounds have relatively high specificity. Meanwhile, a controllable system that can be activated with a switch can probably serve as a convenient tool for further related research.    Photoswitchable chemistry has been applied to a lot of bioactive targets such as ion channels, receptors enzymes and nucleic acids. Recently, the Li group developed CRAC channel inhibitors that can be turned ‘on’ and ‘off’ by UV-light exposure. Scheme 1 . C onverting CRAC channel inhibitors, GSKs , into photoswitchable derivatives, piCRACs . Starting from the well-established GSK-based CRAC inhibitor ( Scheme 1 ), the authors developed a series of nitrosaniline
1 comment
Read more

Proteosome Inhibition Taps Into RNA Splicing

Multiple myeloma (MM) is a malignancy of white blood cells called plasma cells that reside mainly in the bone marrow and is the second most common blood cancer. With increased understanding of biology, the current use of immunomodulatory (IM) drugs and proteasome inhibitors (PI) have taken over the therapeutic landscape for MM. The combination of bortezomib (PI) with lenalidomiede (IM) and dexamethasone is commonly the initial treatment of choice. Early intervention seems to provide a good outcome, but unfortunately, many patients eventually relapse. A major goal in MM treatment is to increase the efficacy of proteasome inhibitors and prevent relapse. To investigate this, Huang et al. used unbiased mass spectrometry-based phosphoproteomics to identify potential vulnerabilities after treatment with the PI carfilzomib and discovered that splicing related proteins had significant changes in phosphorylation that is undetectable upon examination of RNA and protein abundance. Treatment w
Post a Comment
Read more

One Fluorine Atom Fixes Poor KRAS Inhibitors

KRAS  is the most frequently mutated oncogene in human cancer. In the past few decades, the KRAS oncoprotein had always been deemed as an “undruggable target” due to lack of binding surface and tightly binding to its substrate GTP. In 2013, the Shokat group identified that the mutant cysteine KRAS G12C creates a new allosteric pocket “switch-II pocket” which can be exploited to design covalent inhibitors. KRAS G12C accounts for more than 50% of the incidences of KRAS mutations, involving in many cancers, such as non-small cell lung cancer (NSCLC), colorectal adenocarcinomas and pancreatic cancer. KARS G12C has been an attractive target for drug discovery and development in both academia and industry. MRTX849 is a potent, orally available covalent inhibitor of KRAS G12C developed by Mirati Therapeutics and currently undergoing Phase I/II clinical trials. Recently, a paper published in Journal of Medicinal Chemistry reported the design and optimization of MRTX849 . The medi
Post a Comment
Read more