GSE131856
Nuclear receptor ROR? is a targetable master regulator of cholesterol in a subtype of breast cancer [RNA-Seq]
We show that triple-negative breast cancer (TNBC) exhibits a hyper-activated MVA-CB program that is strongly linked to nuclear receptor ROR?, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of ROR? reduces tumor cholesterol contents and synthesis rate while preserving host cholesterol homeostasis. We demonstrate, for the first time, that ROR? functions as a master activator of the entire MVA-CB program, dominantly over SREBP2, through its own direct binding and facilitating the recruitment of SREBP2. ROR? inhibition disrupts its association with SREBP2 and reduces MVA-CB chromatin acetylation. ROR? antagonists cause sustained TNBC tumor regression in patient-derived and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our studies uncover a previously unsuspected master regulator of MVA-CB and an attractive target for TNBC. Overall design: A total of 12 samples were analyzed in this study. The study included two cell lines HCC70 and MDA-MB468. Both Cells were cultured in medium containing vehicle control, XY018 (1.25 or 2.5 µM), atorvastatin (ATV, 1.25 µM) or the combination of XY018 (1.25 µM) and ATV for 24 hours. For MDA-MB468, cells were cultured in growth medium containing vehicle control or GSK805 (2.5 µM) for 24 hours. After treatment, all cells were collected for RNA-Seq assay.