Abstract:Objective To investigate the expression and prognostic value of human epidermal growth factor receptor 2（HER2）in endometrial cancer, and to provide evidence for anti - HER2 targeted therapy in endometrial cancer. Methods （1）Bioinformatics analysis was performed based on datasets from The Cancer Genome Atlas（TCGA）and Gene Expression Omnibus（GEO：GSE115810, GSE120490）to compare HER2 expression levels between normal endometrial tissues and endometrial cancer tissues, and to evaluate its association with survival outcomes.（2）A retrospective cohort study was conducted involving 305 patients with endometrial cancer admitted to Nanjing DrumTower Hospital, the Affiliated Hospital of Nanjing University Medical School, from December 2021 to June 2024.Immunohistochemistry was used to detect the expression levels of HER2, estrogen receptor（ER）, progesterone receptor（PR）, p53, and Ki-67. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model on 130 patients with a follow-up duration of ≥20 months. Results Bioinformatics analysis showed that HER2 expression was significantly higher in endometrial cancer tissues than in normal endometrial tissues（P＜0.01）.Compared with normal tissues, HER2 levels were higher in stage Ⅰ endometrial cancer （P＜0.01）, stage Ⅲendometrial cancer（P=0.01）, and metastatic lesions（P＜0.01）, while no statistically significant differences were observed for stages Ⅱ and Ⅳ（P＞0.05）. In the clinical cohort, 93 patients（30.49%）were HER2-positive, which was significantly associated with multiple adverse clinicopathological characteristics, including age >50 years（P=0.018）, menopause（P＜0.01）, advanced International Federation of Gynecology and Obstetrics（FIGO）stage（Ⅲ/Ⅳ, P=0.03）, poor differentiation（P＜0.01）, lymph node metastasis（P=0.04）, myometrial invasion >1/2（P＜0.01）, and lymphovascular space invasion（P＜0.01）. HER2 expression is related to ER, PR, p53, and Ki-67（P＜0.05）. Patients with positiveHER2 expression are more likely to be ER negative, PR negative, have p53 mutations, and high Ki-67 expression. Patients with HER2 positivity had shorter progression-free survival（PFS）（23.35 months vs 26.04 months, log-rank χ²=11.68, P＜0.01）. Multivariate Cox regression analysis confirmed that HER2 was an independent prognostic factor for PFS in patients with endometrial cancer（OR=5.99, 95%CI：1.12-32.11, P=0.04）.Conclusion High HER2 expression is associated with the expression of ER, PR, p53, and Ki-67 in endometrial cancer, and is closely correlated with adverse clinicopathological characteristics and shorter PFS. HER2 may serve as an independent prognostic biomarker, and anti-HER2 targeted therapy may represent an effective treatment option for patients with HER2-positive endometrial cancer.