AGR3, a member of the protein disulfide isomerase (PDI) family, has been implicated in multiple biological processes related to cancer and respiratory diseases. It is associated with pathways such as Wnt/β -catenin signalling, which is crucial for cancer cell stemness, and may also be involved in epithelial junction regulation in the airway [2,3]. Genetic models, especially knockout models, could potentially provide deeper insights into its functions.

In breast cancer, AGR3 expression is associated with histological grade II, estrogen and progesterone receptor positivity, low ki67 expression, recurrence or distant metastasis, and lumen subtypes. In low and intermediate histological grades, it is related to worse overall and disease-free survival, suggesting it may be a biomarker for early detection and prognosis prediction in luminal subtypes [1]. In colorectal cancer, AGR3 promotes cancer cell stemness by activating the Wnt/β -catenin signalling pathway and promoting β -catenin nuclear translocation, and this effect depends on frizzled 4 (FZD4) [2]. In COPD, AGR3 expression in lung tissue is correlated with the susceptibility to exacerbations. Its down-regulation in patients with frequent exacerbations may lead to decreased expression of adherent and tight junction proteins, increasing the risk of infection and inflammation [3].

In conclusion, AGR3 plays significant roles in cancer progression, especially in breast and colorectal cancers, and in the susceptibility to COPD exacerbations. While direct evidence from gene knockout models is lacking in the provided references, the existing studies suggest that AGR3 is involved in key biological processes related to these diseases, potentially serving as a biomarker and therapeutic target.

References:

1. Moraes, Carolina Leão de, Mendonça, Carolina Rodrigues, Melo, Natália Cruz E, Junior, Jair Pereira de Melo, Amaral, Waldemar Naves do. 2023. Prognostic Impact of AGR3 Protein Expression in Breast Cancer: A Systematic Review and Meta-analysis. In Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia, 45, e609-e619. doi:10.1055/s-0043-1772183. https://pubmed.ncbi.nlm.nih.gov/37944928/

2. Chi, Jiangyang, Zhang, Hongyan, Hu, Jia, Wang, Lin, Wang, Zheng. 2019. AGR3 promotes the stemness of colorectal cancer via modulating Wnt/β-catenin signalling. In Cellular signalling, 65, 109419. doi:10.1016/j.cellsig.2019.109419. https://pubmed.ncbi.nlm.nih.gov/31526829/

3. Ye, Rui, Wang, Cuihong, Sun, Pengbo, Bai, Shuang, Zhao, Li. 2021. AGR3 Regulates Airway Epithelial Junctions in Patients with Frequent Exacerbations of COPD. In Frontiers in pharmacology, 12, 669403. doi:10.3389/fphar.2021.669403. https://pubmed.ncbi.nlm.nih.gov/34177583/