TRIM37 Expression is Associated with Immune Suppression Poor Response to Neoadjuvant Chemotherapy and Worse Survival in ER-Positive/HER2-Negative Breast Cancer.

Abstract

Tripartite motif-containing 37 (TRIM37) is an E3 ubiquitin ligase that epigenetically silences tumor suppressors in DNA repair, regulates polo-like kinase 4, promotes chromosomal instability, and functions as an oncogenic driver in breast cancer (BC). Preclinical studies have implicated TRIM37 in chemotherapy resistance, particularly in triple-negative breast cancer (TNBC), and TRIM37-targeted therapy is in development. However, TRIM37 has not been fully investigated in patients with BC, so its prognostic and therapeutic significance remains unclear. TRIM37 expression was analyzed in 6558 patients across four large, independent cohorts with transcriptome data (METABRIC, TCGA, SCAN-B, and GSE25066). TRIM37 expression was higher in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC than in TNBC, and it was associated with worse disease-free, disease-specific, and overall survival in ER-positive/HER2-negative BC but not in TNBC. TRIM37 expression was significantly associated with DNA repair pathways, homologous recombination deficiency, mutation rates, and enhanced cancer cell proliferation, as evidenced by Nottingham histological grade, Ki67 expression, and gene set enrichment analysis. TRIM37 expression correlated with reduced immune activity, lower cytolytic activity, and decreased response to neoadjuvant chemotherapy in ER-positive/HER2-negative BC, whereas TRIM37-high TNBC displayed higher neoantigen burden and improved chemotherapy response. TRIM37 expression is associated with increased cell proliferation, regardless of subtype; however, it is strongly associated with reduced immune activity, worse response to chemotherapy, and poor prognosis in ER-positive/HER2-negative BC, whereas it was associated with better response to chemotherapy and no relationship with survival in TNBC. Our results provide critical insights into the clinical application of TRIM37-targeted therapies.