大约三分之一接受内分泌治疗的雌激素受体α阳性（ER）乳腺癌（BC）女性由于内在或获得性耐药而面临复发风险。因此，了解 ER BC 内分泌治疗耐药的机制对于改善患者治疗至关重要。线粒体脂肪酸 β-氧化 (FAO) 已被证明是三阴性 BC (TNBC) 中的一个主要代谢途径，可以激活 Src 信号传导。在这里，我们发现代谢重编程会增加ER BC中的FAO，作为内分泌治疗的抵抗机制。在抑制FAO限速酶肉毒碱棕榈酰转移酶1（CPT1）后，从TNBC细胞的转录组学、代谢组学和脂质组学分析中得出代谢相关的整合基因特征，这种源自TNBC的特征与内分泌抵抗显着相关。 ER BC 患者。分子、遗传和代谢组学实验确定了内分泌耐药 ER BC 中 AMPK-FAO 氧化磷酸化 (OXPHOS) 信号的激活。 CPT1敲除或FAO抑制剂在体外和体内的治疗显着增强了ER BC细胞对内分泌治疗的反应。与之前在 TNBC 中的研究结果一致，内分泌治疗诱导的 FAO 激活了 ER BC 中的 Src 通路。 Src抑制剂抑制内分泌耐药肿瘤的生长，并且通过CPT1抑制的代谢启动可以进一步增强疗效。总的来说，这项研究开发并应用了 TNBC 衍生的特征，揭示了对 FAO 的代谢重编程激活了 Src 途径，从而驱动 ER BC 中的内分泌抵抗。

Approximately one-third of endocrine-treated women with estrogen receptor-alpha positive (ER+) breast cancers (BC) are at risk of recurrence due to intrinsic or acquired resistance. Thus, it is vital to understand the mechanisms underlying endocrine therapy resistance in ER+ BC to improve patient treatment. Mitochondrial fatty acid β-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative BC (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER+ BC as a mechanism of resistance to endocrine therapy. A metabolically relevant, integrated gene signature was derived from transcriptomic, metabolomic, and lipidomic analyses in TNBC cells following inhibition of the FAO rate-limiting enzyme carnitine palmitoyl transferase 1 (CPT1), and this TNBC-derived signature was significantly associated with endocrine resistance in ER+ BC patients. Molecular, genetic, and metabolomic experiments identified activation of AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in endocrine-resistant ER+ BC. CPT1 knockdown or treatment with FAO inhibitors in vitro and in vivo significantly enhanced the response of ER+ BC cells to endocrine therapy. Consistent with the previous findings in TNBC, endocrine therapy-induced FAO activated the Src pathway in ER+ BC. Src inhibitors suppressed the growth of endocrine-resistant tumors, and the efficacy could be further enhanced by metabolic priming with CPT1 inhibition. Collectively, this study developed and applied a TNBC-derived signature to reveal that metabolic reprogramming to FAO activates the Src pathway to drive endocrine resistance in ER+ BC.