Oncogenic functions of polypyrimidine tract-binding protein 1 in breast cancer metabolism and progression

Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein that regulates alternative splicing and primarily acts as a splicing repressor. Previous studies have shown that PTBP1 is closely linked to cancer metabolism through regulation by miR-133b and miR-124, which inhibit PTBP1 expression and modulate the splicing of the pyruvate kinase muscle (PKM) gene. Increased PTBP1 expression promotes PKM2 production and enhances glycolysis-dependent metabolism, a hallmark of cancer known as the Warburg effect. Clinical and experimental analyses were conducted to investigate the role of PTBP1 in breast cancer (BC). <i>In silico</i> investigations using The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets revealed a significant association between PTBP1 overexpression and poor prognosis. <i>In vitro</i>, PTBP1 knockdown in BC cell lines (MCF7, SK-BR-3, and MDA-MB-231) increased PKM1 expression and the PKM1/PKM2 ratio, leading to reduced cell proliferation. ATP production increased in MCF7 and SK-BR-3 cells, but not in MDA-MB-231. Although NADH levels were elevated in MCF7 and MDA-MB-231 cells, lactate accumulation was most prominent in MDA-MB-231 cells. qRT-PCR analysis of surgical BC specimens confirmed significantly higher PTBP1 expression in tumour tissues than in adjacent normal breast tissues, with expression positively correlating with tumour grade. These findings collectively demonstrate that PTBP1 is overexpressed in BC and drives cancer-specific metabolic reprogramming associated with the Warburg effect. Therefore, PTBP1 may act as an oncogenic regulator of breast cancer metabolism and serve as a potential therapeutic target.