A master regulator of cholesterol biosynthesis constitutes a therapeutic liability of triple negative breast cancer.

Lipid and cholesterol reprogramming are often observed in specific cancer subtypes. We find that triple-negative breast cancers (TNBCs), but not estrogen receptor-positive (ER+) ones, adopt nuclear receptor RAR-related orphan receptor γ (RORγ) as their new master activator of cholesterol biosynthesis program. Its dominant role over sterol regulatory element-binding protein 2 (SREBP2) renders TNBC highly vulnerable to RORγ inhibitors alone or in combination with statins.