The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development of acquired resistance to targeted therapies in some patients contribute to their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth and survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown to inhibit cancer cell proliferation by disrupting glutaminolysis and inducing oxidative stress. In this study, HER2-positive breast cancer cells were treated with 1E5 to determine their potential inhibitory effects and mechanisms of action in HER2-positive breast cancers. Similar to previous observations in other cancer types, 1E5 treatments inhibited LXR activity, expression, and cancer cell proliferation. Expression of fatty acid synthesis genes, including fatty acid synthase (FASN), was downregulated following 1E5 treatment, and results from co-treatment experiments with an FASN inhibitor suggest that the same pathway is targeted by 1E5. Treatments with 1E5 disrupted glutaminolysis and resulted in increased oxidative stress. Strikingly, HER2 transcript and protein levels were both significantly downregulated by 1E5. Taken together, these findings indicate the therapeutic potential of targeting HER2 overexpression and associated metabolic reprogramming via the modulation of LXR in HER2-positive breast cancers.
HER2阳性亚型约占所有乳腺癌病例的五分之一。部分患者对靶向治疗不敏感及产生获得性耐药，导致其预后不良。HER2过表达与代谢重编程相关，促进癌细胞生长与存活。新型肝X受体（LXR）配体GAC0001E5（1E5）已被证实可通过干扰谷氨酰胺分解并诱导氧化应激来抑制癌细胞增殖。本研究采用1E5处理HER2阳性乳腺癌细胞，以探究其对HER2阳性乳腺癌的潜在抑制效应及作用机制。与先前在其他癌症类型中的观察结果相似，1E5处理可抑制LXR活性、表达及癌细胞增殖。经1E5处理后，脂肪酸合成基因（包括脂肪酸合酶FASN）的表达下调，且与FASN抑制剂的联合处理实验结果表明1E5靶向同一通路。1E5处理干扰了谷氨酰胺分解过程并导致氧化应激增强。值得注意的是，1E5能显著下调HER2转录本及蛋白水平。综上所述，这些发现表明通过调控LXR靶向HER2过表达及相关代谢重编程，在HER2阳性乳腺癌中具有治疗潜力。
肿瘤(癌症)患者之家