The current standard for breast PET imaging is F-FDG. The heterogeneity of F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of F-FDG PET for MYC-overexpressing TNBC. In this study, Zr-transferrin and F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 μM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Head-to-head comparison showed that Zr-transferrin targets TNBC tumors significantly better ( < 0.05-0.001) than F-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and gene expression was decreased upon treatment with BRD4 inhibitors and small interfering RNA ( < 0.01-0.001 for responding cell lines), compared with vehicle treatment. MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells ( < 0.01-0.001). Zr-transferrin targets human TNBC primary tumors significantly better than F-FDG, as shown through PET imaging and biodistribution studies. Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC.