EMP3 Expression in HER2-Enriched Breast Cancer is Linked to PI3K/AKT Signaling and Indicates Poor Prognosis.

purposeEMP3 is closely associated with HER2 expression and trastuzumab resistance. However, the prognostic value of EMP3 in the HER2 subtype remains poorly understood. It is necessary to clarify the relationship between EMP3 and prognosis in HER2-enriched breast cancer.

methodsThe expression of EMP3 was measured using immunohistochemistry staining. Then, Chi-square tests were carried out to investigate the relationship between EMP3 and relevant clinical data. After that, univariable and multivariable Cox regression were used to filter out factors with independent prognostic value, while a nomogram was constructed to forecast the disease-free survival (DFS) rates of patients. Subsequently, we employed R to identify genes exhibiting a correlation coefficient exceeding 0.6 with EMP3 expression and then mapped such genes onto the PI3K-AKT pathway through the KEGG database. Patients were then stratified into two subgroups based on the median EMP3 expression, and differential expression status of the PI3K-AKT pathway between the groups was analyzed. The proliferation capacity under trastuzumab treatment was detected through plate colony formation and EdU incorporation assays in cells with different EMP3 expression levels. Nude mouse xenograft tumor formation experiments were employed to further verify the connection between EMP3 expression and trastuzumab resistance.

resultsA total of 90 HER2-enriched breast cancer patients were enrolled in this research. EMP3 expression did not exhibit any significant association with age, menopausal status, T-stage, N-stage, androgen receptor, Ki67, EGFR, or CK5/6. Results from univariate and multivariate Cox regression analysis confirmed that EMP3 expression, T-stage, and N-stage served as independent prognostic factors for DFS. The prognostic model constructed based on EMP3 expression, T-stage, and N-stage has good predictive power. The model's C-index was measured to be 0.745. The calibration curves of the model largely coincided with the diagonal line, suggesting that the actual DFS of patients was almost the same as the DFS predicted by the model. The genes positively associated with EMP3 expression status bear a close association with the PI3K-AKT pathway among HER2-enriched breast cancers. Enhanced activation of the PI3K-AKT pathway was detected in the EMP3 high-expression group. Results derived from both in vitro and in vivo experiments demonstrate that EMP3 regulates the PI3K/AKT pathway and promotes resistance to trastuzumab.

conclusionsHigh EMP3 expression in HER2-enriched breast cancer predicts poor patient outcomes. Overexpression of EMP3 exerts an upregulatory effect on the PI3K-AKT pathway and boosts the development of trastuzumab resistance.