Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer, but there is currently no treatment that specifically targets this subset of the disease. Studies by a team at Case Western Reserve University now suggest that patients with TNBC may benefit from treatment using the cytokine interferon-β (IFN-β). Their studies have shown that IFN-β inhibits TNBC migratory cancer stem cells (CSCs) in vitro, while data from existing human databases suggests that higher levels of IFN-β in TNBC correlate with improved recurrence-free survival.

“We demonstrate that IFN-β reverses some of the more aggressive features of triple-negative breast cancer, which are responsible for metastasis and therapy-failure,” comments Mary Doherty, at Case Western Reserve School of Medicine. “Moreover, we found that evidence of IFN-β in TNBC tumors correlates with improved patient survival following chemotherapy.”

The researchers, who report their findings in the Proceedings of the National Academy of Sciences (PNAS), are advocating clinical trials to test the effects of treatment using IFN-β in addition to chemotherapy and radiotherapy in TNBC patients. Their published paper is entitled “Interferon-Beta Represses Cancer Stem Cell Properties in Triple-Negative Breast Cancer.”

TNBC lacks estrogen, progesterone, and HER2 receptors and commonly doesn’t respond to chemotherapy. Tumor recurrence and metastasis cause the majority of patient deaths, the Case Western team reports. Metastatic TNBC tumors contain cells that exhibit epithelial–mesenchymal (E-M) plasticity, which prior research has demonstrated can lead to the emergence of highly migratory, mesenchymal/cancer stem cells (Mes/CSCs). It is these cells that are resistant to chemotherapy and lead to the development of new tumors. “While chemotherapy kills the majority of tumor cells, it fails to eliminate a subset of cancer cells, called cancer stem cells,” Doherty continues. “The survival of these cancer stem cells following therapy is believed to be responsible for therapy failure in patients.”

Prior studies have also suggested that IFN signaling plays a key role in regulating TNBC plasticity. The latest in vitro work by the Case Western researchers and collaborators at the Cleveland Clinic Foundation and Stanford University School of Medicine has now shown that IFN-β can directly target these cancer stem cells and prevent them from migrating. In laboratory tests, they found that then numbers of migrating stem cells was halved, even two days after withdrawing exposure to IFN-β. Their studies also indicated that exposure to IFN-β repressed mesenchymal markers and reduced anchorage-independent growth and tumor sphere formation.

When the team then mined existing human datasets, they found that increased expression of genes activated by IFN-β was associated with better recurrence-free survival in TNBC. Patients with increased levels of IFN-β were about 25% less likely to experience a recurrence than patients with low levels “These findings suggest that IFN-β plays a positive, critical role in TNBC outcome,” the authors write. Further evaluation of clinical data indicated that the metagene signature associated with IFN-β activity was also associated with a repressed CSC metagene signature, “demonstrating that IFN-β within the breast TME [tumor microenvironment] not only has potent immune modulatory functions but also regulates CSC properties by repressing CSC-specific target genes.”

The researchers claim their findings provide “important clinical evidence to suggest that IFN-β–related signaling is necessary for repressing aggressive CSC-like properties in TNBC.” They are now investigating how IFN-β modulates the immune system to exert its anticancer effects. They also aim to carry out clinical trials evaluating IFN-β therapy for TNBC, using nanoparticle technology to deliver IFN-β directly to the Mes/CSCs, before chemotherapy or radiotherapy is started. “Our future studies will examine improved methods of IFN-β delivery to the tumor site incorporating nanoparticle technology,” Doherty states.


 








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