The current standard for breast PET imaging is ¹⁸F-FDG. The heterogeneity of ¹⁸F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. ¹⁸F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm³. 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 ⁸⁹Zr 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 ⁸⁹Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of ¹⁸F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, ⁸⁹Zr-transferrin and ¹⁸F-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. Results: Head-to-head comparison showed that ⁸⁹Zr-transferrin targets TNBC tumors significantly better (P < 0.05–0.001) than ¹⁸F-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 TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA (P < 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 (P < 0.01–0.001). Conclusion: ⁸⁹Zr-transferrin targets human TNBC primary tumors significantly better than ¹⁸F-FDG, as shown through PET imaging and biodistribution studies. ⁸⁹Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC.

乳腺PET成像的当前标准是¹⁸ F-FDG。乳腺癌中¹⁸ F-FDG摄取的异质性限制了其效用，在受体状态，组织病理学亚型和增殖标志物之间差异很大。¹⁸ F-FDG PET通常表现出非特异性内在化和低特异性和敏感性，特别是对于小于1 cm ^3的肿瘤。MYC是一种参与肿瘤发生的蛋白质，在三阴性乳腺癌（TNBC）中过表达。转铁蛋白受体（TfR）的表面表达增加是MYC上调的下游事件，已被证实是分子成像的临床相关靶标。转铁蛋白标记为⁸⁹Zr已在临床前成功鉴定出许多癌症亚型中的MYC状态，并已显示可通过靶向MYC和PI3K信号通路的小分子抑制剂治疗预测癌基因状态的响应和变化。我们假设⁸⁹ Zr-转铁蛋白PET将无创地检测MYC和TfR，并改进了过表达MYC的TNBC的¹⁸ F-FDG PET的当前标准。方法：本研究中，⁸⁹ Zr-转铁蛋白和¹⁸ Zr-转铁蛋白在TNBC的临床前模型中比较了F-FDG成像。TNBC细胞（MDA-MB-157，MDA-MB-231和Hs578T）用含溴结构域的蛋白4（BRD4）抑制剂JQ1和OTX015（0.5-1μM）处理。测定细胞增殖，基因表达和蛋白质表达以探索这些抑制剂对MYC和TfR的作用。结果：头-头比较表明，⁸⁹ Zr的转显著更好靶向肿瘤TNBC（P <0.05-0.001）高于¹⁸在MDA-MB-231和F-FDG通过PET成像和生物分布研究的MDA-MB-157异种移植物以及TNBC的患者异种移植模型。用BRD4抑制剂和c-MYC治疗后c-Myc和TfR基因表达降低与媒介物处理相比，干扰RNA较小（对于应答细胞系，P <0.01-0.001）。在MDA-MB-231和MDA-MB-157细胞中进行药物治疗后，MYC和TfR蛋白表达以及受体介导的转铁蛋白内在化也显着降低（P <0.01-0.001）。结论： PET成像和生物分布研究表明，^89种Zr-转铁蛋白对人TNBC原发肿瘤的靶向作用明显优于¹⁸ F-FDG。⁸⁹ Zr-转铁蛋白是一种有用的工具，可通过TNBC中以TfR为靶点的PET成像检查MYC。