AR-PDEF 通路通过促进 MAD1 降解促进 ER 阴性乳腺癌肿瘤增殖和上调 MYC 介导的基因转录。
AR-PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer.
机构信息
Department of Breast Cancer Pathology and Research Laboratory, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
出版信息
Mol Cancer. 2018 Sep 14;17(1):136. doi: 10.1186/s12943-018-0883-0.
BACKGROUND
Androgen receptor (AR) is expressed in 60%~ 70% oestrogen receptor (ER)-negative breast cancer (BC) cases and promotes the growth of this cancer subtype. Expression of prostate-derived Ets factor (PDEF), a transcription factor, is highly restricted to epithelial cells in hormone-regulated tissues. MYC and its negative regulator MAD1 play an important role in BC progression. Previously, we found that PDEF expression is strongly correlated with AR expression. However, the relationship between AR and PDEF and the function of PDEF in ER-negative BC proliferation are unclear.
METHODS
AR and PDEF expression in ER-negative BC tissues and cell lines was determined by performing immunohistochemistry or western blotting. Protein expression levels and location were analysed by performing western blotting, RT-qPCR and immunofluorescence staining. Co-immunoprecipitation and chromatin immunoprecipitation assays were performed to validate the regulation of AR-PDEF-MAD1-MYC axis. Moreover, the effect of AR and PDEF on BC progression was investigated both in vitro and in vivo.
RESULTS
We found that PDEF was overexpressed in ER-negative BC tissues and cell lines and appeared to function as an oncogene. PDEF expression levels were strongly correlated with AR expression in ER-negative BC, and PDEF transcription was positively regulated by AR. PDEF upregulated MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative BC. Finally, we found that compared with the inhibition of AR expression alone, simultaneous inhibition of AR and PDEF expression further suppressed tumour proliferation both in vitro and in vivo.
CONCLUSIONS
Our data highlight the role of the AR-PDEF-MAD1-MYC axis in BC progression and suggest that PDEF can be used as a new clinical therapeutic target for treating ER-negative BC.
背景
雄激素受体（AR）在 60%~70%雌激素受体（ER）阴性乳腺癌（BC）病例中表达，并促进这种癌症亚型的生长。前列腺衍生的 Ets 因子（PDEF）是一种转录因子，其表达高度局限于激素调节组织中的上皮细胞。MYC 及其负调节因子 MAD1 在 BC 进展中发挥重要作用。此前，我们发现 PDEF 的表达与 AR 的表达强烈相关。然而，AR 和 PDEF 之间的关系以及 PDEF 在 ER 阴性 BC 增殖中的功能尚不清楚。
方法
通过免疫组织化学或 Western blot 检测 ER 阴性 BC 组织和细胞系中 AR 和 PDEF 的表达。通过 Western blot、RT-qPCR 和免疫荧光染色分析蛋白质表达水平和位置。进行共免疫沉淀和染色质免疫沉淀实验以验证 AR-PDEF-MAD1-MYC 轴的调控。此外，还在体外和体内研究了 AR 和 PDEF 对 BC 进展的影响。
结果
我们发现 PDEF 在 ER 阴性 BC 组织和细胞系中过表达，似乎起致癌基因的作用。PDEF 的表达水平与 ER 阴性 BC 中的 AR 表达强烈相关，并且 AR 正向调节 PDEF 的转录。PDEF 通过促进 MAD1 降解在上皮细胞中上调 MYC 介导的基因转录。最后，我们发现与单独抑制 AR 表达相比，同时抑制 AR 和 PDEF 的表达在体外和体内进一步抑制肿瘤增殖。
结论
我们的数据强调了 AR-PDEF-MAD1-MYC 轴在 BC 进展中的作用，并表明 PDEF 可用作治疗 ER 阴性 BC 的新临床治疗靶点。
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