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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)

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