The transcription factor RIP140 regulates interferon γ signaling in breast cancer

Abstract

ABSTRACTRIP140 (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. We identified the interferon γ (IFNγ) signaling as being substantially repressed by RIP140 knock-down. Using theGBP1(guanylate binding protein 1) gene as a reporter of IFNγ signaling, we demonstrated its robust induction by RIP140 through an ISRE motif, leading to a significant reduction of its induction upon IFNγ treatment. Furthermore, we showed that low levels of RIP140 amplified the IFNγ-dependent inhibition of BC cell proliferation. In line with these data, reanalysis of transcriptomic data obtained in human BC samples, revealed that IFNγ levels were 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 new regulator of IFNγ signaling in breast tumorigenesis.