Clinical, pathological and gene expression profling of estrogen receptor discordance in breast cancer

• Xi Wang ^[1] ; Shengnan Bao ^[1] ; Mengping Jiang ^[1] ; Xian Zou ^[1] ; Yongmei Yin ^[2]
  1. [1] Nantong University

     Nantong University

     China

     
  2. [2] Nanjing Medical University

     Nanjing Medical University

     China

     
• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 27, Nº. 1, 2025, págs. 233-256
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Background Breast cancer (BC) is the world’s largest tumor species in which hormone receptor-positive patients have relatively good prognosis. However, majority of patients will develop late resistance, one of the important factors is due to the loss of the original estrogen receptor (ER) expression.

    Methods We conducted this study in 115 patients with BC who experienced second biopsy at Jiangsu Province Hospital (JSPH) and divided patients into two subgroups ER+to – and ER+to+. First, clinicopathological characteristics between two groups were evaluated. Second, we explored candidate genes related to BC ER intratumor heterogeneity by applying next-generation sequencing (NGS) in 42 patients. Multi-omics integrative analysis of tumor transcriptomic, cancer-related pathway, diagnostic and prognostic value and immune profle were conducted. Besides, preliminary assay were also used to evaluate the correlation between KMT2C and ERα (ESR1) expression. The CCK-8, 5-Ethynyl-2′-deoxyuridine (EdU) assays, Transwell assays and the wound scratch tests were applied to explore the cellular interactions between KMT2C and BC.

    Results We fnd the histological type (p=0.008) and disease-free survival (DFS) (p=0.004) were signifcantly diferent in two subgroups. In Cox survival analysis, metastasis (Hazard ratio (HR)>1, p=0.007) and neo-adjuvant (HR<1, p<0.001) are independent prognostic factors of DFS. Besides, by analyzing NGS results, we found four genes KMT2C, FGFR19, FGF1 and FGF4 were highly mutated genes in ER+to−subgroup. Furthermore, the gene KMT2C displayed signifcant diagnostic value and prognostic value in BC and pan-cancer. In addition, a positive correlation between KMT2C expression and immune infltrating levels of T cell CD4+, macrophage and neutrophil was found. In the end, Western blot and RT-qPCR assay were used and found KMT2C and ERα (ESR1) expressions are strongly positive correlated in mRNA and protein level. Inhibition of KMT2C signifcantly reduced proliferation, invasion, and migration of MCF7 cells.

    Conclusion People in two cohorts from JSPH presented diferent clinical characteristics and prognosis. The gene KMT2C may afect the progression of BC by regulating the molecular, epigenetic activity and immune infltration. It may also serve as a novel prognostic biomarker for BC patients who underwent ER status converted from positive to negative.