Shpigel Jessica, Luciano Emilia F, Ukandu Blessing, Sauane Moira, de la Parra Columba
Department of Chemistry, Herbert H. Lehman College, City University of New York, New York, NY 10468, USA.
Department of Biological Sciences, Herbert H. Lehman College, City University of New York, New York, NY 10468, USA.
Int J Mol Sci. 2025 Jan 16;26(2):733. doi: 10.3390/ijms26020733.
Breast cancer treatment has advanced significantly, particularly for estrogen receptor-positive (ER+) tumors. Tamoxifen, an estrogen antagonist, is widely used; however, approximately 40% of patients develop resistance. Recent studies indicate that microRNAs, especially miR-155, play a critical role in this resistance. Our analysis of MCF-7 tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) cells revealed that miR-155 is significantly upregulated in TAM-R cells. Overexpression of miR-155 in TAM-S cells increased resistance to tamoxifen. Additionally, genistein, a natural isoflavone from soybeans, effectively downregulated miR-155 and its targets associated with apoptosis and glucose metabolism, including STAT3 and hexokinase 2 (HK2). Notably, genistein also significantly decreased cell migration, suggesting potential anti-metastatic effects. Furthermore, genistein reduced glucose consumption, indicating its potential to overcome miR-155-mediated tamoxifen resistance and modulate the Warburg effect. These findings highlight genistein as a promising therapeutic agent for overcoming tamoxifen resistance in ER+ breast cancer and merit further investigation.
乳腺癌治疗已经取得了显著进展，尤其是对于雌激素受体阳性（ER+）肿瘤。他莫昔芬作为一种雌激素拮抗剂被广泛使用；然而，约40%的患者会产生耐药性。最近的研究表明，微小RNA，尤其是miR-155，在这种耐药性中起关键作用。我们对MCF-7他莫昔芬敏感（TAM-S）和他莫昔芬耐药（TAM-R）细胞的分析显示，miR-155在TAM-R细胞中显著上调。在TAM-S细胞中过表达miR-155会增加对他莫昔芬的耐药性。此外，染料木黄酮，一种来自大豆的天然异黄酮，有效地下调了miR-155及其与细胞凋亡和糖代谢相关的靶标，包括信号转导和转录激活因子3（STAT3）和己糖激酶2（HK2）。值得注意的是，染料木黄酮还显著降低了细胞迁移，表明其具有潜在的抗转移作用。此外，染料木黄酮减少了葡萄糖消耗，表明其有潜力克服miR-155介导的他莫昔芬耐药性并调节瓦伯格效应。这些发现突出了染料木黄酮作为克服ER+乳腺癌中他莫昔芬耐药性的一种有前景的治疗剂，值得进一步研究。
