获得性化疗耐药是三阴性乳腺癌（TNBC）治疗的主要挑战。尽管积累的证据表明 microRNA-21 (miR-21) 是肿瘤进展的重要调节因子，但 miR-21 在调节 TNBC 多药耐药性中的作用仍不清楚。在这项研究中，我们证明 miR-21 通过调节 P-糖蛋白 (P-gp) 药物外排泵来影响 4T1 TNBC 细胞对阿霉素 (DOX) 的化疗耐药性。 4T1 细胞中 miR-21 的过度表达显着降低了它们对 DOX 的敏感性，阻止了 DOX 促进的细胞死亡。我们采用与 PD-L1 结合肽 (P21) 缀合的抗 miR-21 寡核苷酸来靶向递送至 4T1 肿瘤细胞。 4T1 TNBC 中 miR-21 的选择性下调导致通过上调磷酸酶和张力蛋白同源物 (PTEN) 逆转 P-gp 介导的 DOX 耐药性。我们的研究强调，miR-21 是 TNBC 药物流出泵的关键调节因子，靶向 miR-21 可以增强 DOX 敏感性，为 DOX 耐药 TNBC 患者提供潜在的治疗选择。版权所有 © 2024 Eun Hye Kim 等人。

Acquired resistance to chemotherapy is a major challenge in the treatment of triple-negative breast cancer (TNBC). Despite accumulated evidence showing microRNA-21 (miR-21) as a vital regulator of tumor progression, the role of miR-21 in modulating the multidrug resistance of TNBC remains obscure. In this study, we demonstrate that miR-21 affects chemoresistance in 4T1 TNBC cells in response to doxorubicin (DOX) by regulating the P-glycoprotein (P-gp) drug efflux pump. Overexpression of miR-21 in the 4T1 cells markedly reduced their sensitivity to DOX, impeding DOX-promoted cell death. We employed anti-miR-21 oligonucleotide conjugated with a PD-L1-binding peptide (P21) for targeted delivery to 4T1 tumor cells. The selective down-regulation of miR-21 in 4T1 TNBC led to the reversal of P-gp-mediated DOX resistance by up-regulating phosphatase and tensin homolog (PTEN). Our study highlights that miR-21 is a key regulator of drug efflux pumps in TNBC, and targeting miR-21 could enhance DOX sensitivity, offering a potential therapeutic option for patients with DOX-resistant TNBC.Copyright © 2024 Eun Hye Kim et al.