Distinct Expression Patterns and Clinical Associations of the IRX Gene Family Across Hormone-Sensitive Cancers

<b>Background/Objectives:</b> The Iroquois (<i>IRX</i>) family of homeobox genes regulates critical developmental processes, and emerging evidence suggests that their dysregulation contributes to cancer progression, particularly in relation to cancer stemness. Although their expression appears to be influenced by hormonal regulation, their potential roles in hormone-sensitive cancers remain incompletely understood. <b>Methods:</b> In this study, we performed a comprehensive, exploratory analysis of all six Iroquois genes (<i>IRX1</i>-<i>IRX6</i>) across prostate, breast, ovarian, and endometrial cancers. Using large-scale publicly available transcriptomic datasets, we systematically examined <i>IRX</i> gene expression patterns and their associations with tumour progression, prognosis, hormone regulation, drug response, and cancer stemness. <b>Results:</b><i>IRX3</i> and <i>IRX5</i> were consistently elevated in estrogen-dependent tumours and <i>IRX</i>2 and <i>IRX</i>4 were notably upregulated in prostate cancer. Despite evidence of estrogen receptor 1 (ESR1) and androgen receptor (AR) binding near several <i>IRX</i> promoters, estrogen treatment assays showed that ESR1 binding at promoters alone was insufficient to induce <i>IRX</i> transcription. Clinically, <i>IRX</i>2 expression was associated with favourable outcomes in breast, endometrial, and ovarian cancers and showed correlations with stemness-related signatures in prostate cancer. Similarly, <i>IRX</i>4 expression was associated with stemness features in prostate and endometrial cancers. In addition, <i>IRX</i>6 expression showed associations with reduced sensitivity to abiraterone, suggesting a potential link with therapeutic resistance in these tumours. <b>Conclusions:</b> Collectively, these findings highlight the context-dependent expression patterns and clinical associations of <i>IRX</i> genes across hormone-driven cancers. While largely correlative, this study provides a framework for future functional investigations and suggests that selected <i>IRX</i>s may have potential utility as biomarkers for disease stratification and treatment response in hormone-sensitive cancers.