ABSTRACT Triple-negative breast cancers (TNBC) still lack effective targeted therapy, despite the fact that TNBC often presents as invasive diseases with poor outcome. Subtypes of TNBC show rare or low pathological complete response (pCR) rates to neoadjuvant chemotherapies. Despite the newly acquired tumor genomics data, readily actionable, therapy-effective targets are yet to be revealed or established. Our recent data mining and other tumor analysis revealed that RORC/RORγ, an orphan member of the nuclear receptor family of transcription factors, is amplified or overexpressed in over 30% of TNBC and that its overexpression is significantly associated with poor outcomes. Our functional studies revealed that it is required for growth and survival of TNBC cells, and that its inhibitors, developed recently by us, are highly effective in killing TNBC cells selectively and stopping tumor growth and metastasis at relatively low doses, without overt toxicity. With other preliminary studies, we hypothesize that overexpression and/or hyperactivation of RORγ drives TNBC progression through a novel cholesteromic feed-forward loop and that targeting RORγ with a potent tumor-selective, small-molecule inhibitor, either alone or in combination with chemotherapy, can be a novel and effective therapeutic strategy for TNBC. The hypothesis will be tested in 3 specific aims: Aim 1 will establish that overexpressed RORγ drives tumor growth and therapeutic resistance through its function in reprogramming lipid/cholesterol metabolism; Aim 2 will establish that induction of an epigenetic switch underlies the superior anti-TNBC potency of the RORγ inhibitor, and Aim 3 will thoroughly examine the anti-tumor efficacy of the optimized inhibitor using PDX and other tumor models. Successful completion of the proposed studies should, for the first time, establish RORγ as a new, major driver of TNBC and effective therapeutic target.