Abstract
<div>Abstract<p>Approximately one-third of endocrine-treated women with estrogen receptor alpha–positive (ER<sup>+</sup>) breast cancers 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<sup>+</sup> breast cancer to improve patient treatment. Mitochondrial fatty acid β-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative breast cancer (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER<sup>+</sup> breast cancer 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 patients with ER<sup>+</sup> breast cancer. Molecular, genetic, and metabolomic experiments identified activation of AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in endocrine-resistant ER<sup>+</sup> breast cancer. CPT1 knockdown or treatment with FAO inhibitors <i>in vitro</i> and <i>in vivo</i> significantly enhanced the response of ER<sup>+</sup> breast cancer cells to endocrine therapy. Consistent with the previous findings in TNBC, endocrine therapy–induced FAO activated the Src pathway in ER<sup>+</sup> breast cancer. 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<sup>+</sup> breast cancer.</p>Significance:<p>Increased fatty acid oxidation induced by endocrine therapy activates Src signaling to promote endocrine resistance in breast cancer, which can be overcome using clinically approved therapies targeting FAO and Src.</p></div>
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