Abstract
BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in women, primarily due to distant metastasis. Metabolic reprogramming plays a critical role in tumor growth and spread, but the metabolic mechanisms underlying metastasis in breast cancer remain unclear. The primary objective of this study is to identify molecular targets mediating breast cancer progression and to evaluate whether targeting the metabolic reprogramming represents a potential therapeutic strategy. METHODS: To uncover key metabolic regulators involved in breast cancer progression, we analyzed high-throughput RNA sequencing data and identified Paired Like Homeodomain 1 (PITX1) as a frequently upregulated oncogene. Its expression was further validated by immunohistochemistry, quantitative PCR, and western blotting across various metastatic breast cancer tissues. The correlation between PITX1 expression and patient survival was also evaluated. Functional assays were conducted to explore the role of PITX1 in promoting breast cancer proliferation and metastasis. As this study is primarily based on mechanistic cellular and bioinformatic analyses rather than clinical intervention trials, traditional clinical effect size metrics are not directly applicable. However, we have now ensured that all major findings include quantitative effect measurements (e.g., fold changes, hazard ratios where applicable, correlation coefficients) together with corresponding statistical significance values to improve clarity and transparency. RESULTS: Elevated PITX1 expression was significantly associated with poorer overall survival, distant metastasis-free survival, relapse-free survival, and post-progression survival in breast cancer patients. Silencing PITX1 significantly reduced breast cancer cell proliferation and suppressed glycolysis. Mechanistically, we found that PITX1 transcriptionally activates Phosphofructokinase platelet (PFKP), a key glycolytic enzyme, thereby enhancing glycolytic flux to promote tumor growth and metastatic capacity. Notably, isoliquiritigenin was identified as a small-molecule inhibitor that targets the PITX1-PFKP axis, downregulating glycolysis and consequently suppressing breast cancer progression. CONCLUSION: Our findings uncover a novel oncogenic mechanism by which PITX1 promotes breast cancer progression and metastasis through glycolytic reprogramming. Targeting the PITX1-PFKP axis with isoliquiritigenin offers a promising therapeutic strategy for breast cancer treatment.