Lysine-Specific Demethylase 1 (LSD1) Modulates Hypoxia and Antitumor Immunity Pathways in Triple Negative Breast Cancer

Epigenetic alterations can disrupt gene functions and lead to cellular neoplastic transformation, significantly contributing to cancer initiation and progression, including triple-negative breast cancer (TNBC). Inhibitors of lysine-specific demethylase 1 (LSD1) have shown potential antineoplastic activity, yet their utility as a biomarker and specific roles in TNBC remain underexplored. Utilizing tissue microarrays from 389 TNBC patients at Singapore General Hospital, we performed immunohistochemical analysis of LSD1 and integrated our findings with data from three additional cohorts (TCGA, METABRIC, FUSCC). Our results reveal that elevated LSD1 levels correlate with poorer survival outcomes in TNBC patients. Mechanistically, LSD1 was found to activate HIF-1/VEGFA signaling and impair cell cycle regulation, thus promoting tumor progression. The causal role of LSD1 was validated through functional assays, RNA-sequencing, and ChIP-sequencing on human breast cell lines and patient-derived xenograft organoids. Additionally, employing digital spatial profiling with whole transcriptome analysis, we discovered that LSD1 overexpression dampens immune-cell profiles and anti-tumor immunity pathways. Overall, our findings elucidate the oncogenic role of LSD1 in TNBC, highlighting implications for potential therapeutic avenues to regulate tumor immunity dynamics and improve patient outcomes.