Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment.

中文翻译：

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胆固醇和甲羟戊酸：通过 ERRα 途径参与乳腺癌进展和耐药性的两种代谢物。


乳腺癌是女性癌症相关死亡的第二大原因。对内分泌治疗或化疗的耐药性是一个限制性缺点。在这种背景下，这项工作旨在评估胆固醇和甲羟戊酸在肿瘤进展过程中的作用及其对当今使用的临床治疗产生耐药性的贡献。在这项研究中，我们证明胆固醇和甲羟戊酸治疗能够激活雌激素相关受体 α (ERRα) 通路，增加过氧化物酶体增殖物激活受体 γ 共激活剂 1-α (PGC-1α)、ERbB2/人的表达水平乳腺癌细胞中的上皮受体 (HER2)、肿瘤蛋白 D52 (TPD52) 和 NOTCH2 蛋白。该通路的激活被证明与强烈的代谢转换、更高的增殖率、持续的运动性、癌症干细胞样细胞 (CSC) 的增殖和脂滴的形成有关。所有这些事件都与更大的肿瘤增殖、侵袭性和耐药性有关。此外，胆固醇或甲羟戊酸治疗诱导的蛋白质激活和表达与从MCF-7/TAMr细胞系获得的结果一致，该细胞系主要用作获得性内分泌治疗耐药性的乳腺癌模型。总而言之，我们的数据表明胆固醇和甲羟戊酸是两种代谢物，通过激活 ERRα 途径与乳腺癌进展、侵袭性和耐药性有关。我们的研究结果使我们能够将 ERRα 受体确定为乳腺癌患者的不良预后标志物，这表明胆固醇/甲羟戊酸与 ERRα 之间的相关性可以作为乳腺癌治疗的新的可能靶点。