Opperman Reid Morgan, Maiti Sujit, Majumder Mousumi
Department of Biology, John R. Brodie Science Centre, Brandon University, 270 18th Street, Brandon, MB, R7A6A9, Canada.
Sci Rep. 2025 Sep 29;15(1):33584. doi: 10.1038/s41598-025-18719-y.
Doxorubicin is an effective treatment for breast cancer, but drug resistance poses a significant challenge. Emerging regulators of drug resistance include microRNAs, small non-coding RNAs. Two miRNAs, miR-526b and miR-655, promote aggressive breast cancer phenotypes like cell proliferation, cancer stem cell upregulation, altered response to oxidative and metabolic stress and help tumor metastasis by activating COX-2/EP4/PI3K pathways. However, their impact on the effects of chemotherapeutic treatments remains unexplored. This study investigates the impact of overexpressing miR-526b and miR-655 on doxorubicin responses in breast cancer, focusing on pro-survival, apoptotic, and DNA-damage response pathways. We confirm the role of PI3K/Akt signalling in promoting cell survival and resistance in response to doxorubicin in vitro, though key differences exist between each cell line. High-throughput analysis of doxorubicin-exposed breast cancer cell lines, revealing novel mechanisms of miR-526b and miR-655. Overexpression of miR-526b and miR-655 may alter doxorubicin efficacy through mechanisms like DNA damage response changes, metabolic reprogramming, and immune pathway activation. Further investigation may uncover new therapeutic strategies to improve treatment efficacy and patient outcomes.
多柔比星是乳腺癌的一种有效治疗方法，但耐药性构成了重大挑战。新出现的耐药调节因子包括微小RNA（microRNAs），即小的非编码RNA。两种微小RNA，miR-526b和miR-655，可促进侵袭性乳腺癌表型，如细胞增殖、癌症干细胞上调、对氧化和代谢应激反应的改变，并通过激活COX-2/EP4/PI3K途径帮助肿瘤转移。然而，它们对化疗治疗效果的影响仍未得到探索。本研究调查了miR-526b和miR-655过表达对乳腺癌多柔比星反应的影响，重点关注促生存、凋亡和DNA损伤反应途径。我们证实了PI3K/Akt信号在体外促进细胞存活和对多柔比星耐药中的作用，尽管每个细胞系之间存在关键差异。对多柔比星处理的乳腺癌细胞系进行高通量分析，揭示了miR-526b和miR-655的新机制。miR-526b和miR-655的过表达可能通过DNA损伤反应改变、代谢重编程和免疫途径激活等机制改变多柔比星的疗效。进一步的研究可能会发现新的治疗策略，以提高治疗效果和患者预后。
