Estrogen-mediated NF-κB blockade enables breast cancer sensitivity to oncolytic VSV virotherapy

Novel therapies are urgently needed for breast Cancer. While our previous work investigating the use of oncolytic viruses against the disease demonstrated its promise, heterogeneous responses were observed. Interestingly, breast Cancer is classified into subtypes based on the expression of hormone receptors. We noted that triple-negative breast cancers (TNBCs), which lack the expression of the estrogen (E2) receptor (ER) were resistant to the oncolytic vesicular stomatitis virus (oVSV), whereas ER⁺ cancers were particularly sensitive. We found that E2 stimulation enhanced virus Infection, while E2-antagonizing endocrine therapies counteract the virus. Further mechanistic studies revealed a defect of nuclear factor (NF)-κB activation with E2 stimulation. With the goal of enhancing oncolytic virotherapy independently of E2, we designed a treatment strategy that combines oVSV with the NF-κB inhibitors IKK16 and sulfasalazine and found that both drugs improved virus replication in TNBC cell lines and patient samples. Our data uncover a novel impact of E2 on oncolytic virotherapy and demonstrate that combining virus treatment with NF-κB inhibitors recapitulates the E2-mediated virus enhancement. Importantly, our treatment combinations could be beneficial to all breast cancers, including TNBCs, as well as Other breast cancers that do not respond to E2.