Association of Enolase-1 with Prognosis and Immune Infiltration in Breast Cancer by Clinical Stage

Abstract

Purpose Enolase-1 (ENO1) plays a key role in malignancies. Previous studies on the association between ENO1 expression and breast cancer prognosis had yielded inconsistent results. In the present study, we assessed the prognostic effect of ENO1 in breast cancer using Guangzhou Breast Cancer Study (GZBCS) cohort with full consideration of the potential confounders and the modification effects. The results were further validated in the TCGA-BRCA cohort and explained by tumor immunity. Methods ENO1 protein expressions were evaluated by immunohistochemistry in tissue microarrays from 961 patients with primary invasive breast cancer. Chi-square tests were used to assess the association of ENO1 levels with the patient’s characteristics. Cox regression models were applied to assess the prognostic effects. The TCGA-BRCA cohort was utilized to validate the results and explore the potential mechanisms. The immune infiltration was determined using the CIBERSORT and ssGSEA algorithms; the correlation between ENO1 expression and the abundance of tumor-infiltrating immune cells (TIICs) and scores of immune-related functions was evaluated by Wilcoxon signed-rank tests and Spearman’s rank test. Results ENO1 protein expression exerted a protective effect on OS in stage I/II patients (HR=0.58, 95% CI: 0.35–0.96) but not in stage III patients (HR=1.42, 95% CI: 0.81–2.49, P interaction =0.04) in GZBCS; consistent results were obtained at mRNA levels in TCGA cohort. Immune infiltration analyses revealed that ENO1 was positively correlated with multiple antitumor TIICs (including M1 macrophages, B cells, CD8 T cells, T helper 2 cells, and NK cells) only in stage I/II but not stage III patients. Conclusion A higher expression of ENO1 was associated with a better prognosis only in early-stage breast cancer, which may be related to the different effects of ENO1 on immune infiltration, suggesting that ENO1 may be a promising target for precision immunotherapy in breast cancer.

ENO1 as a biomarker of breast cancer progression and metastasis – a bioinformatic approach

“…The poor prognostic effect is observed in advanced (Stage 3) disease, and is present in HER-2 positive and triple negative breast cancers. Our data agrees with previous recent studies showing an association of high ENO1 expression with the aggressive basal subtype and a favourable prognosis in patients with early stage breast cancer but not with advanced stage disease and/or basal breast cancer [16,26,38]. We also observed that methylation of the gene is associated with a good prognostic effect, consistent with the expected effect from reducing ENO1 gene expression.…”

“…A complex relationship of ENO1 with immune pathways was revealed by this study to complement other studies evaluating the role of ENO1 in the tumour-immune microenvironment [13,38,39]. Underexpression occurs in good prognostic subtypes of breast carcinoma, whereas overexpression of the pathways occurs in triple negative breast carcinomas.…”

“…Clustering of ENO1 across the pathways we examined was also observed in DCIS, indicating that the gene plays a role from the earliest stages of breast cancer development. A complex relationship of ENO1 with immune pathways was revealed by this study to complement other studies evaluating the role of ENO1 in the tumour-immune microenvironment [13,38,39]. Underexpression occurs in good prognostic subtypes of breast carcinoma, whereas overexpression of the pathways occurs in triple negative breast carcinomas.…”