Abstract
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer as it shows a high capacity for metastasis and poor prognoses. Metabolic reprogramming is one of the hallmarks of cancer, and aberrant glycolysis was reported to be upregulated in TNBC. Thus, identifying metabolic biomarkers for diagnoses and investigating cross-talk between glycolysis and invasiveness could potentially enable the development of therapeutics for patients with TNBC. In order to determine novel and reliable metabolic biomarkers for predicting clinical outcomes of TNBC, we analyzed transcriptome levels of glycolysis-related genes in various subtypes of breast cancer from public databases and identified a distinct glycolysis gene signature, which included ENO1, SLC2A6, LDHA, PFKP, PGAM1, and GPI, that was elevated and associated with poorer prognoses of TNBC patients. Notably, we found a transcription factor named Y-box-binding protein 1 (YBX1) to be strongly associated with this glycolysis gene signature, and it was overexpressed in TNBC. A mechanistic study further validated that YBX1 was upregulated in TNBC cell lines, and knockdown of YBX1 suppressed expression of those glycolytic genes. Moreover, YBX1 expression was positively associated with epithelial-to-mesenchymal transition (EMT) genes in breast cancer patients, and suppression of YBX1 downregulated expressions of EMT-related genes and tumor migration and invasion in MDA-MB-231 and BT549 TNBC cells. Our data revealed an YBX1-glycolysis-EMT network as an attractive diagnostic marker and metabolic target in TNBC patients.
Highlights
Gain-of-function and loss-of-function studies further validated that Y-box-binding protein 1 (YBX1) regulated glycolysis- and epithelial-to-mesenchymal transition (EMT)-related gene expressions and was crucial for tumor invasiveness, indicating that YBX1 exhibits clinical diagnostic value and is a potential metabolic target for triplenegative breast cancer (TNBC)
We identified that YBX1 acts as an upstream regulator to regulate glycolysis and EMT gene expressions
YBX1 is elevated in a variety of malignancies, including breast cancer; the prognostic role of YBX1 in TNBC is unclear
Summary
Breast cancer is the most commonly diagnosed malignancy in women, and breast cancer is divided into luminal, human epidermal receptor 2 (HER2)-enriched, and triplenegative breast cancer (TNBC) subtypes, according to the presence of distinct molecular markers, including the estrogen receptor (ER), progesterone receptor (PR), and HER2. TNBC, which is characterized by the absence of the ER, PR, and HER2, is the most malignant subtype of breast cancer [1,2]. Due to a deficiency of efficient therapeutic targets and its aggressive features, such as resistance to chemotherapy, higher invasiveness, and a strong tendency to metastasize, patients with TNBC have poorer survival outcomes than non-TNBC patients [3,4]. Exploring novel biomarkers is urgently needed to improve the accuracy of diagnoses and efficacy of treatments for TNBC patients
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