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

TL;DR

This study explores how IRX genes behave in hormone-sensitive cancers like breast and prostate cancer, finding that their expression patterns may predict tumor behavior and treatment response.

Contribution

The study reveals distinct IRX gene expression patterns and their associations with cancer progression, stemness, and drug resistance in hormone-sensitive cancers.

Findings

IRX3 and IRX5 are elevated in estrogen-dependent tumors, while IRX2 and IRX4 are upregulated in prostate cancer.

IRX2 and IRX4 expression correlates with favorable outcomes and stemness features in multiple cancers.

IRX6 expression is linked to reduced sensitivity to abiraterone, suggesting a role in therapeutic resistance.

Abstract

Hormone-sensitive cancers such as prostate, breast, ovarian, and endometrial cancers are governed by hormone signals and often show differential responses to treatment. Understanding the genes involved in these cancers will help explain why some tumours behave more aggressively or become resistant to therapy. The Iroquois (IRX) gene family is known to play important roles during development, but their importance in hormone-sensitive cancers is not well understood. In this study, we analyzed large public datasets to examine how IRX genes are expressed in different hormone-sensitive cancers and how their expression correlates to disease progression, patient outcomes, cancer stem-like features, and treatment response. We found that IRX genes show distinct patterns depending on cancer type. These findings provide a useful resource for researchers and highlight that IRX genes may act as potential markers of tumour behaviour that warrant further investigation.

Background/Objectives: The Iroquois (IRX) 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. Methods: In this study, we performed a comprehensive, exploratory analysis of all six Iroquois genes (IRX1–IRX6) across prostate, breast, ovarian, and endometrial cancers. Using large-scale publicly available transcriptomic datasets, we systematically examined IRX gene expression patterns and their associations with tumour progression, prognosis, hormone regulation, drug response, and cancer stemness. Results:
IRX3 and IRX5 were consistently elevated in estrogen-dependent tumours and IRX2 and IRX4 were notably upregulated in prostate cancer. Despite evidence of estrogen receptor 1 (ESR1) and androgen receptor (AR) binding near several IRX promoters, estrogen treatment assays showed that ESR1 binding at promoters alone was insufficient to induce IRX transcription. Clinically, IRX2 expression was associated with favourable outcomes in breast, endometrial, and ovarian cancers and showed correlations with stemness-related signatures in prostate cancer. Similarly, IRX4 expression was associated with stemness features in prostate and endometrial cancers. In addition, IRX6 expression showed associations with reduced sensitivity to abiraterone, suggesting a potential link with therapeutic resistance in these tumours. Conclusions: Collectively, these findings highlight the context-dependent expression patterns and clinical associations of IRX genes across hormone-driven cancers. While largely correlative, this study provides a framework for future functional investigations and suggests that selected IRXs may have potential utility as biomarkers for disease stratification and treatment response in hormone-sensitive cancers.

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