The role of Iroquois-class homeobox genes in cancer stemness

Introduction:
Cancer poses a global challenge due to aggressive metastasis, treatment resistance, and relapse, often driven by cancer stem cells (CSCs). CSCs evade conventional therapies, emphasizing the need for CSC-targeted strategies. The Iroquois homeobox (IRX) gene family is linked to cancer stemness, but the exact roles and therapeutic potential of IRX genes in CSC promotion remain unclear.

Methods:
Normalized gene expression data from all six IRX genes were downloaded from publicly available databases. A comparison of IRX expression with cancer stages and drug sensitivity was conducted. All data processing and analysis were performed using GraphPad Prism (10.0.2). A Student t-test was used to compare difference between two groups and a one-way ANOVA test was applied to compare multiple groups. The functional role of these IRXs in CSC regulation will be assessed using in vitro and in vivo models.

Results:
In silico analyses revealed an elevated expression of Iroquois homeobox 3 (IRX3) and Iroquois homeobox 5 (IRX5) in castration-resistant prostate cancer (PCa) patient samples and patient-derived xenografts (PDXs) compared to primary tumours, with further upregulation after enzalutamide treatment. Gene set enrichment analysis identified significant enrichment of stemness-associated gene signatures in PCa patients with high IRX3 expression. Additionally, expression data revealed IRX5 upregulation with therapy resistance in several breast cancer (BCa) cell lines. Future studies will explore the roles of IRX3 and IRX5 in CSC maintenance, tumour progression, metastasis, and therapeutic resistance in PCa and BCa models.

Conclusions:
Given the link between CSCs, therapy resistance, and metastasis, we hypothesize that elevated IRX3 and IRX5 expression contributes to CSC maintenance in PCa and BCa. If validated, these IRXs could serve as novel therapeutic targets, inhibiting CSC-driven tumour growth and progression. This would represent a significant advancement, as no therapies currently target CSCs and ultimately preventing metastasis, drug resistance, and relapse in PCa and BCa patients.