Identification of potential key genes that respond to capsaicin treatment in ER-positive breast cancer: An integrated analysis

Abstract

Capsaicin, a natural compound, has demonstrated antitumor efficacy in estrogen receptor-positive breast cancer (ER-positive BC). However, its downstream molecular targets and mechanisms remain poorly understood, particularly those linked to metabolic reprogramming and immune modulation. This study aimed to identify capsaicin-responsive genes and explore their roles in ER-positive BC progression and tumor microenvironment remodeling. Bioinformatic analysis was performed on the GSE64155 dataset from GEO to screen differentially expressed genes (DEGs) in capsaicin-treated ER-positive BC. Functional enrichment (GO/KEGG) and protein-protein interaction (PPI) network analyses were performed to prioritize key genes. Experimental validation included qPCR and Western blotting to assess gene and protein expression in capsaicin-treated cells. Clinical relevance was evaluated using TCGA expression data, survival analysis (overall survival [OS], relapse-free survival [RFS], and distant metastasis-free survival [DMFS]), and immunohistochemistry (IHC) in BC tissues. Immune cell infiltration was analyzed via the CIBERSORT algorithm. SHMT2 and GARS were identified as the most significant capsaicin-responsive genes. Both genes were overexpressed in BC tissues and may be associated with a poor prognosis in patients with ER-positive BC. Capsaicin significantly reduced SHMT2 and GARS expression at the mRNA and protein levels. Immune infiltration analysis indicated that high SHMT2 and GARS expression may be associated with altered immune cell infiltration patterns. This study identifies SHMT2 and GARS as novel downstream targets of capsaicin in ER-positive BC and links their known oncogenic functions to a potential new mechanism underlying the antitumor effects of capsaicin.