Zhang Qiang, Liu Xiao-Yan, Li Shuang, Zhao Zhao, Li Juan, Cui Ming-Ke, Wang En-Hua
Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, PR China.
Department of Pathology, College Basic Medical Science, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyan, 110042, PR China.
Biochem Biophys Res Commun. 2017 Oct 21;492(3):425-433. doi: 10.1016/j.bbrc.2017.08.082. Epub 2017 Aug 24.
Transcriptional silencing of estrogen receptor α (ERα) expression is an important etiology contributing to the letrozole-resistance in ERα-positive breast cancer (BCa) cells, but the transcription factors responsible for this transcriptional repression remain largely unidentified. Here we report that the expression of the basic helix-loop-helix myogenic regulatory factor MYOD was abnormally up-regulated in letrozole-resistant BCa tissues and in experimentally-induced letrozole-resistant BCa cells. Overexpression of the exogenous MYOD impaired ERα expression and potentiated letrozole-resistance in letrozole-sensitive MCF7 cells, whereas MYOD knockdown could effectively restore ERα expression and thereby promote letrozole-sensitivity in letrozole-resistant MCF-7/LR cells. Mechanistically, MYOD was shown to be a potent corepressor of ESR1 transcription, and this transcriptional repression was significantly enhanced in the presence of letrozole treatment. Thus, targeted inhibition of MYOD may restore ERα level and lead to resensitization to letrozole-based hormone therapy, providing a novel therapeutic strategy for relapsed ERα-positive BCa patients. Our data also underscore an unexpected chemotherapeutic facet of MYOD, which may operate as a novel regulator of BCa biology.
雌激素受体α（ERα）表达的转录沉默是导致ERα阳性乳腺癌（BCa）细胞对来曲唑耐药的重要病因，但负责这种转录抑制的转录因子在很大程度上仍未明确。在此，我们报告称，碱性螺旋-环-螺旋肌源性调节因子MYOD的表达在来曲唑耐药的BCa组织以及实验诱导的来曲唑耐药BCa细胞中异常上调。外源性MYOD的过表达损害了ERα的表达，并增强了来曲唑敏感的MCF7细胞对来曲唑的耐药性，而敲低MYOD可有效恢复ERα的表达，从而促进来曲唑耐药的MCF-7/LR细胞对来曲唑的敏感性。从机制上讲，MYOD被证明是ESR1转录的有效共抑制因子，并且在来曲唑处理的情况下，这种转录抑制作用显著增强。因此，靶向抑制MYOD可能会恢复ERα水平，并导致对基于来曲唑的激素疗法重新敏感，为复发的ERα阳性BCa患者提供一种新的治疗策略。我们的数据还强调了MYOD意想不到的化疗方面，它可能作为BCa生物学的一种新型调节因子发挥作用。
