Despite the efficacy of tamoxifen in preventing disease relapse, a large portion of breast cancer patients show intrinsic or acquired resistance to tamoxifen, leading to treatment failure and unfavorable clinical outcome. MYB proto-oncogene like 2 (MYBL2) is a transcription factor implicated in the initiation and progression of various human cancers. However, its role in tamoxifen resistance in breast cancer remained largely unknown. In the present study, by analyzing public transcriptome dataset, we found that MYBL2 is overexpressed in breast cancer and is associated with the poor prognosis of breast cancer patients. By establishing tamoxifen-resistant breast cancer cell lines, we also provided evidence that MYBL2 overexpression contributes to tamoxifen resistance by up-regulating its downstream transcriptional effectors involved in cell proliferation (PLK1, PRC1), survival (BIRC5) and metastasis (HMMR). In contrast, inhibiting those genes via MYBL2 depletion suppresses cancer progression, restores tamoxifen and eventually reduces the risk of disease recurrence. All these findings revealed a critical role of MYBL2 in promoting tamoxifen resistance and exacerbating the progression of breast cancer, which may serve as a novel therapeutic target to overcome drug resistance and improve the prognosis of breast cancer patients.

尽管他莫昔芬具有预防疾病复发的功效，但很大一部分乳腺癌患者对他莫昔芬表现出内在或获得性耐药，导致治疗失败和不利的临床结果。MYB 原癌基因样 2 (MYBL2) 是一种转录因子，与各种人类癌症的发生和进展有关。然而，它在乳腺癌中他莫昔芬耐药中的作用仍然未知。在本研究中，通过分析公共转录组数据集，我们发现 MYBL2 在乳腺癌中过度表达，并且与乳腺癌患者的不良预后有关。通过建立耐他莫昔芬的乳腺癌细胞系，我们还提供了证据表明 MYBL2 过表达通过上调其参与细胞增殖（PLK1、PRC1）、存活（BIRC5）和转移（HMMR）的下游转录效应子来促进他莫昔芬抗性。相比之下，通过消除 MYBL2 来抑制这些基因会抑制癌症进展，恢复他莫昔芬并最终降低疾病复发的风险。所有这些发现揭示了 MYBL2 在促进他莫昔芬耐药和加剧乳腺癌进展中的关键作用，这可能成为克服耐药性和改善乳腺癌患者预后的新治疗靶点。恢复他莫昔芬并最终降低疾病复发的风险。所有这些发现揭示了 MYBL2 在促进他莫昔芬耐药和加剧乳腺癌进展中的关键作用，这可能成为克服耐药性和改善乳腺癌患者预后的新治疗靶点。恢复他莫昔芬并最终降低疾病复发的风险。所有这些发现揭示了 MYBL2 在促进他莫昔芬耐药和加剧乳腺癌进展中的关键作用，这可能成为克服耐药性和改善乳腺癌患者预后的新治疗靶点。