Increased Protein and Transcript Expression Levels of Lysine-Specific Demethylase 1 (LSD1) Signify Worse Prognosis in Triple-Negative Breast Cancer

Epigenetic alterations can lead to altered gene functions and cellular neoplastic transformation, contributing to cancer initiation and progression. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase in 2004, has increasingly been shown to be overexpressed in various cancers and to regulate carcinogenesis. Thus, this study aims to investigate the effects of LSD1 protein and transcript in triple-negative breast cancer (TNBC) while evaluating its association with clinicopathological parameters and survival outcomes. A total of 389 TNBC cases diagnosed at the Department of Anatomical Pathology, Singapore General Hospital from 2003 to 2014 were used. Tissue microarrays were constructed, and immunohistochemistry was performed using an antibody against LSD1. LSD1 transcript (KDM1A) levels and their association with survival outcomes were assessed in three cohorts (METABRIC, TCGA, FUSCC). Differentially expressed genes (DEGs) between the LSD1 and KDM1A sample groups were identified using Welch’s t-tests with multiple testing corrections. A total of 80.7% of TNBC patients expressed LSD1 protein, which was significantly associated with shorter overall survival (P = 0.036). Four genes (ELOC, COPS5, MTDH, VEGFR1) were further revealed to be upregulated in LSD1+ TNBCs, while a higher COPS5 and ELOC expression was found to be significantly associated with worse OS. Increased KDM1A levels were additionally associated with worse disease-free survival (P = 0.019) in TCGA. A total of 2135 overlapping genes were found to be differentially expressed between KDM1A high-low TNBCs, with significantly enriched functions involved in cell proliferation pathways (cell cycle, DNA replication). Our results support the prognostic significance of increased LSD1 protein expression to be associated with poorer survival in TNBC patients. The identification of both LSD1/KDM1A-associated DEGs and their key relationship with oncogenic pathways further support aberrant LSD1 epigenetic expression in influencing TNBC heterogeneity. Overall, the study warrants the role of LSD1 as a potential TNBC target.