PROX1 expression is significantly associated with ERG expression and the TMPRSS2-ERG fusion gene in prostate cancer

Abstract Background: Lineage plasticity enables prostate cancer cells to bypass androgen receptor (AR) dependence, contributing to metastasis, treatment resistance, and lethality. The developmental transcription factor PROX1 was recently identified as an early driver of lineage plasticity. The TMPRSS2-ERG fusion, a common genomic event in prostate cancer, induces ERG overexpression and aggressive tumor behavior. We investigated the relationship between PROX1 expression and ERG expression in the context of TMPRSS2-ERG fusion in prostate cancer. Methods: We analyzed data from The Cancer Genome Atlas (TCGA) Prostate Adenocarcinoma (PRAD) dataset (n = 492 samples). The UCSC Xena Browser was used to visualize and integrate gene expression, copy number alterations, and fusion status. Complementary analyses were performed using cBioPortal. Genomic instability was assessed using both fraction of the genome altered (FGA) and mutation count. The correlation between PROX1 and ERG expression was evaluated in fusion-positive and fusion-negative tumors. Results: PROX1 expression showed a strong positive correlation with ERG expression in TMPRSS2-ERG fusion-positive tumors (r = 0.4, p = 3.2 X 10⁻¹⁶). Fusion-positive samples exhibited elevated PROX1 expression, whereas fusion-negative samples had lower expression. This pattern suggests that PROX1 induction is associated with ERG-driven transcriptional reprogramming linked to the TMPRSS2-ERG fusion. Conclusion: PROX1 expression is significantly associated with ERG expression and TMPRSS2-ERG fusion status in prostate cancer. These findings reinforce the role of PROX1 as an early marker and potential mediator of lineage plasticity. Targeting PROX1 or its regulatory pathways may offer a novel therapeutic strategy to mitigate plasticity-driven progression and treatment resistance in TMPRSS2-ERG fusion-positive prostate cancer.