Endometrial cancer (EC) is a common malignant tumor of the female reproductive system in the world. For most of the treated patients, although the survival rate is improved, most patients still have a poor prognosis. The pathogenesis of EC has always been a strong scientific focus, but there is no clear conclusion. Therefore, in view of modularization, this study is to conduct an in‐depth analysis on the effects of estrogen receptor alpha (ERα) regarding EC. The purpose is to identify the molecular course of EC. We obtained 10 co‐expression modules, in which ANO2, EMP3, and other genes are significantly differentially expressed in patients with EC. Additionally, there are active regulatory effects in dysfunction modules, thus genes such as ANO2 and EMP3 would be identified as key genes, which are associated with the development of EC. Enrichment results showed that the module genes were significantly involved in RNA splicing, covalent chromatin modification, histone modification, and organelle fission, and other biological processes, as well as significantly regulated mitogen‐activated protein kinases (MAPK) signaling pathway, Endocytosis, Rap1 signaling pathway, and viral carcinogenesis, and other signaling pathways. Finally, we identified noncoding RNA pivot including FENDRR, miR‐520c‐3p. Besides, transcription factors pivot including NFKB1, E2F1, and RELA which significantly regulate dysfunction module genes. Overall, our work deciphered a co‐expression network involving differential gene regulation in ERα‐associated EC. It helps reveal the core modules and potential regulatory factors of the diseases and enhances our understanding of the pathogenesis. More importantly, we revealed that ERα activates the MAPK signaling pathway to promote the development of EC. It helps to provide a new reference for later research.
