The transcription factor RIP140 regulates interferon γ signaling in breast cancer

RIP140 (receptor interacting protein of 140 kDa) is an important player in breast cancer (BC) by regulating key cellular pathways such as nuclear hormone receptors signaling. In order to identify additional genes specifically regulated by RIP140 in BC, we performed an RNA sequencing after silencing its expression in MCF-7 cells. Many genes were isolated including the vitamin D receptor, whose regulation was validated by qPCR. Most importantly, interferon γ (IFNγ) signaling was substantially controled by RIP140. We identified GBP1 (guanylate binding protein 1), a prime IFNγ effector, as robustly stimulated by RIP140 through an ISRE motif, while IFNγ-dependent expression of GBP1 was repressed by the transcriptional coregulator. Furthermore, we showed that RIP140 modulated IFNγ-dependent repression of BC cell proliferation. Finally, reanalysis of transcriptomic data revealed that IFNγ expression was associated with good prognosis only for BC patients exhibiting tumors expressing low levels of RIP140, thus confirming its effect on the anti-tumor activity of IFNγ provided by our experimental data. Altogether, this study identifies RIP140 as a major regulator of IFNγ signaling in breast tumorigenesis.