Mitochondrial Calcium Uniporter in Breast Cancer: The Clinical Prediction Value in Asians and the Involvement in the Shaping of Metastatic Niche

Breast cancer (BC) is the most commonly diagnosed cancer among women. The cause of death of BC is primarily related to cancer metastasis. Mitochondrial calcium uniporter (MCU) complex is a key regulator of the accumulation of mitochondrial Ca^(2+). However, the multi-omic understanding of the diagnostic/prognostic relevance of MCU and its involvement in tumor metastasis remain inconclusive. This study aimed to explore the diagnostic/prognostic significance of MCU and identify the possible mechanisms underlying the BC metastasis. The Cancer Genome Atlas (TCGA) sourced multi-omic analysis was conducted to examine the clinical significance of MCU and its potential mechanisms. The BC tumor showed significantly increased MCU expression levels compared to normal tissue. The high expression of MCU showed no difference among various cancer staging. Higher MCU in BC than in normal tissue was observed in Caucasian and Asian populations, but not in the African population. BC patients with high MCU expression had a shorter survival time than patients with low MCU expression. The prognostic prediction showed statistical significance in the Asian population, grade 3 tumor, Th1-enriched/Th2-decreased tumor. Gene Set Enrichment Analysis (GSEA) identified three core enrichment genes: ITGB1, LOX, and ANTXR1. The protein-protein interaction (PPI)network showed the enriched functions mainly participate in a protein complex involved in cell adhesion, mitochondrial Ca^(2+) homeostasis, extracellular matrix organization, and the cell leading edge. In conclusion, this study unveiled the significance of MCU in diagnosis/prognosis in the Asian population and provided mechanistical insights on metastasis-related ECM remodeling.

關鍵字

Breast cancer ； Mitochondrial calcium uniporter ； Metastasis ； Diagnosis ； Prognosis ； Multi-omics

並列摘要

背景目的：乳癌是女性中最常被診斷出的癌症。乳癌的死因主要與癌症轉移有關。粒線體鈣離子單向轉運子（MCU）複合物是粒線體鈣離子積累的關鍵調節分子。然而，MCU的診斷／預後相關性及其參與腫瘤轉移的多體學理解仍然沒有定論。本研究旨在探討MCU的診斷／預後意義，並確定乳癌轉移的可能機制。方法：運用癌症基因組圖譜（TCGA）數據來源的多體學分析研究MCU的臨床意義及其潛在機制。結果：與正常組織相比，BC腫瘤顯示出顯著增加的MCU表達水平。MUC的高表達在各種癌症分期之間沒有差異。在高加索人和亞洲人中觀察到乳癌中的MCU高於正常組織，但在非洲人則無。具高MCU表達的乳癌患者的生存時間比具有低MCU表達的患者短。預後預測在亞洲、3級腫瘤、Th1富集／Th2減少的腫瘤中顯示出統計學意義。基因富集分析（GSEA）鑑定出核心富集基因：ITGB1、LOX和ANTXR1。蛋白質－蛋白質相互作用（PPI）網絡表明，富集的功能主要參與蛋白質複合物，參與細胞粘附、粒線體鈣離子穩態、細胞外基質組織和細胞前沿。總結本研究揭示了MCU在亞洲人群診斷／預後中的意義，並為轉移相關的細胞外基質重塑提供了機制見解。

並列關鍵字

乳癌；粒線體鈣離子單向轉運子；轉移；診斷；預後；多體學

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