| Summary: | The mesenchymal sub-type of triple negative breast cancer (MES-TNBC) has a highly aggressive behavior and worse prognosis, due to its invasive and stem-like features, that correlate with metastatic dissemination and resistance to therapies. Furthermore, MES-TNBC is characterized by the expression of molecular markers related to the epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs). The altered expression of α<sub>v</sub>β<sub>3</sub> integrin has been well established as a driver of cancer progression, stemness, and metastasis. Here, we showed that the high levels of α<sub>v</sub>β<sub>3</sub> are associated with MES-TNBC and therefore exploited the possibility to target this integrin to reduce the aggressiveness of this carcinoma. To this aim, MES-TNBC cells were treated with a novel peptide, named ψRGDechi, that we recently developed and characterized for its ability to selectively bind and inhibit α<sub>v</sub>β<sub>3</sub> integrin. Notably, ψRGDechi was able to hamper adhesion, migration, and invasion of MES-TNBC cells, as well as the capability of these cells to form vascular-like structures and mammospheres. In addition, this peptide reversed EMT program inhibits mesenchymal markers. These findings show that targeting α<sub>v</sub>β<sub>3</sub> integrin by ψRGDechi, it is possible to inhibit some of the malignant properties of MES-TNBC phenotype.
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