Receptor-interacting protein kinase 3 (RIP3 or RIPK3) is a central player in “programmed” or “regulated” necrotic cell death pathway. Here we show that programmed necrosis is activated in response to chemotherapeutic agents and contributes to chemotherapy-induced breast cancer cell death. However, we also show that RIP3 expression is silenced in basal like breast cancer cell lines due to DNA methylation near its transcription start site. Due to this silencing mechanism, loss of RIP3 expression in these cells leads to resistance to DNA damaging-agents. Hypomethylating agents restore RIP3 expression and promote sensitivity not only to death receptor ligands, but also to a surprising diversity of standard chemotherapeutic agents in a RIP3-specific manner. Our data indicates that RIP3-dependent breast cancer cell death is activated in response to DNA damaging-agents. This suggests that RIP3 plays a greater role in response to DNA damaging-agents than has been previously appreciated, we propose that hypomethylating agents, in combination with standard chemotherapy, may be useful in treating breast cancers that lack RIP3 expression.
