Hsu Yi-Chiang, Lee Kuan-Ting, Pei Sung-Nan, Rau Kun-Ming, Tsai Tai-Hsin
School of Medicine, I-Shou University, Kaohsiung 824, Taiwan.
Graduate Institutes of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Curr Issues Mol Biol. 2025 Aug 5;47(8):622. doi: 10.3390/cimb47080622.
Triple-negative breast cancer (TNBC) is a highly aggressive and therapeutically challenging subtype of breast cancer due to its lack of estrogen receptors, progesterone receptors, and HER2 (Human epidermal growth factor receptor 2) expression, which severely limits available treatment options. Recently, Simvastatin-a widely used HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor for hyperlipidemia-has garnered interest for its potential anticancer effects. This study investigates the therapeutic potential of Simvastatin in triple-negative breast cancer (TNBC). The results demonstrate that Simvastatin significantly inhibits the proliferation of TNBC cells, particularly MDA-MB-231, in a dose- and time-dependent manner. Mechanistically, Simvastatin primarily induces G1 phase cell cycle arrest to exert its antiproliferative effects, with no significant evidence of apoptosis or necrosis. These findings support the potential repositioning of Simvastatin as a therapeutic agent to suppress TNBC cell growth. Further analysis shows that Simvastatin downregulates cyclin-dependent kinase 4 (CDK4), a key regulator of the G1/S cell cycle transition and a known marker of poor prognosis in breast cancer. These findings highlight a novel, apoptosis-independent mechanism of Simvastatin's anticancer action in TNBC. Importantly, given that many breast cancer patients also suffer from hyperlipidemia, Simvastatin offers dual therapeutic benefits-managing both lipid metabolism and tumor cell proliferation. Thus, Simvastatin holds promise as an adjunctive therapy in the treatment of TNBC and warrants further clinical investigation.
三阴性乳腺癌（TNBC）是一种侵袭性很强且治疗具有挑战性的乳腺癌亚型，因其缺乏雌激素受体、孕激素受体以及HER2（人表皮生长因子受体2）表达，这严重限制了可用的治疗选择。最近，辛伐他汀——一种广泛用于治疗高脂血症的HMG-CoA（3-羟基-3-甲基戊二酰辅酶A）还原酶抑制剂——因其潜在的抗癌作用而受到关注。本研究调查了辛伐他汀在三阴性乳腺癌（TNBC）中的治疗潜力。结果表明，辛伐他汀以剂量和时间依赖性方式显著抑制TNBC细胞的增殖，尤其是MDA-MB-231细胞。从机制上讲，辛伐他汀主要诱导G1期细胞周期停滞以发挥其抗增殖作用，没有明显的凋亡或坏死证据。这些发现支持将辛伐他汀重新定位为抑制TNBC细胞生长的治疗药物的潜力。进一步分析表明，辛伐他汀下调细胞周期蛋白依赖性激酶4（CDK4），CDK4是G1/S细胞周期转换的关键调节因子，也是乳腺癌预后不良的已知标志物。这些发现突出了辛伐他汀在TNBC中抗癌作用的一种新的、不依赖凋亡的机制。重要的是，鉴于许多乳腺癌患者也患有高脂血症，辛伐他汀具有双重治疗益处——既能管理脂质代谢又能控制肿瘤细胞增殖。因此，辛伐他汀有望作为TNBC治疗的辅助疗法，值得进一步进行临床研究。
