Identification of the role of transcription factor ETV7 in breast cancer aggressiveness

This study focuses on ETV7, a transcriptional repressor, known to be up-regulated in breast cancer (BC). Firstly, we demonstrated a new role of ETV7 in promoting breast cancer stem-like cell (BCSC) plasticity and resistance to chemotherapy in BC cells. We observed that ETV7 repressed a large panel of interferon response genes and increased BCSC cell plasticity, leading to resistance to 5-fluorouracil. Then, we investigated the role of ETV7 in inflammatory and immune responses in BC cells. We identified TNFRSF1A, encoding for TNFR1, as one of the genes repressed by ETV7. We demonstrated that ETV7 directly bound to the intron I of this gene, and we showed that the ETV7-mediated down-regulation of TNFRSF1A reduced the activation of NF-κB signaling. These results suggest that ETV7 can reduce the inflammatory responses in BC cells by repressing the TNFR1/NF-κB axis. Moreover, we analyzed the role of ETV7 in the regulation of antigen presentation and confirmed that ETV7 downregulated genes involved in the antigen-presenting pathway, potentially leading to cancer immune evasion We also analyzed if the silencing of ETV7 affected the viability of cancer cells and observed that knock-down of ETV7 can induce p53-mediated apoptosis in cancer cells. Lastly, we analyzed the pro-tumorigenic potential of ETV7 using in vivo model and we observed that mammary gland tumor cells overexpressing ETV7 formed bigger tumors with higher proliferation potential. Taken collectively, the data acquired during this project confirm the role of ETV7 as an important regulator of BC aggressiveness both in vitro and in vivo and propose ETV7 as a novel player in BC immunity, opening a new research direction and giving useful insights for more effective therapeutic strategies.