Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in diagnosis and treatment of breast cancer (BRCA). The histone modification has been found to be related to the progression of cancer. This study aimed to probe the low HER2 expression BRCA heterogeneity by histone modification genes. The BRCA data and cell lines were collected from The Cancer Genome Atlas database. Weighted gene co-expression network analysis and non-negative matrix factorization clustering were jointly applied to obtain BRCA clusters. The expression of hub histone modification gene was detected using western blot assay. The gene ontology term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to reveal functional information. The overall survival analysis was performed using survival and survminer packages, and the immune landscape was mainly analyzed using CIBERSORT software. Totally 43 histone modification genes correlated with survival of BRCA patients with HER2 low expression were screened. Based on these 43 histone modification genes, the BRCA samples were classified into cluster1, cluster2 and cluster3. Histone modification gene NFKBIZ exhibited high expression, while RAD51 demonstrated low expression in low HER2 expression BRCA cell. Cluster1 exhibited the best prognosis, while cluster3 had the worse outcomes. Tumor mutational burden (TMB) was remarkably increased in cluster3 group compared to cluster1 and cluster2. Moreover, the relative proportion of 16 immune cell infiltration and 8 immune checkpoint expression were remarkably differential among cluster1, cluster2 and cluster3, and the drug sensitivity exhibited difference among cluster1, cluster2 and cluster3 in BRCA patients with low HER2 expression. This study identified three HER2 low expression BRCA clusters with different characteristics based on histone modification genes. The TMB, immune cell infiltration, immune checkpoints and drug sensitivity were different among the three clusters.