SLC7A5/E2F1/PTBP1/PKM2 axis mediates progression and therapy effect of triple-negative breast cancer through the crosstalk of amino acid metabolism and glycolysis pathway

Triple-negative breast cancer (TNBC) is one of the most challenging malignancies with the highest mortality rates among women. TNBC relies on both amino acid metabolism and glycolysis to fuel its bioenergetic and biosynthetic demand. However, the potential crosstalk between these two metabolic pathways and its impact on TNBC progression remains largely unexplored. In this study, we observed that SLC7A5, a key amino acid transporter, was upregulated in TNBC and strongly associated with poor patient prognosis. We demonstrated that the elevated SLC7A5 expression activated the amino acid pathway and promoted cell proliferation, tumor growth, and therapeutic resistance by inducing the switch from PKM1 to PKM2 expression, thereby mediating the crosstalk between amino acid metabolism and glycolysis. We further identified that the upregulation of SLC7A5 resulted from miR-152 suppression, which regulates TNBC cellular function and tumor growth. In addition, miR-152/SLC7A5 axis mediated the expression of PTBP1, which maintains the balance between PKM1 and PKM2, linking amino acid signaling with the glycolysis pathway. To further understand the mechanism of PTBP1 upregulation, we identified that E2F1 transcriptionally activated PTBP1 expression through direct binding at the seed site, while E2F1 expression was also induced by SLC7A5 in TNBC. This novel SLC7A5/ E2F1/PTBP1 axis plays a crucial role in regulating the crosstalk between amino acid signaling and glycolysis in TNBC and is essential for TNBC progression and therapeutic effectiveness. Our findings offer valuable insights into the molecular mechanisms underlying TNBC metabolic reprogramming and highlight potential targets for future therapeutic interventions. • SLC7A5 promotes TNBC proliferation and therapy resistance via metabolic crosstalk. • SLC7A5 drives the switch from PKM1 to PKM2 expression. • SLC7A5–E2F1 axis activates PTBP1 transcription to increase PKM2 expression. • miR-152 downregulation directly increases SLC7A5 expression to foster TNBC progression. • SLC7A5/E2F1/PTBP1 axis drives TNBC metabolic reprogramming and therapy response.