Association of increased primary breast tumor with decreased disease-specific survival.

OBJECTIVE

Tumor expression of Anterior Gradient 2 (), an endoplasmic reticulum protein disulfide isomerase, was associated with decreased breast cancer survival. We aimed to validate the association of tumor mRNA expression with disease-specific survival (DSS) and identify differentially expressed signaling pathways between high and low expression tumor groups.

METHODS

Primary tumor mRNA expression data from the METABRIC study was used to evaluate expression as a prognostic factor for DSS while adjusting for survival-determining confounders using Cox proportional-hazards regression. Differentially expressed genes and signaling pathway differences between high and low groups were determined by modular enrichment analyses using DAVID and Ingenuity Pathway Analysis.

RESULTS

Increased tumor mRNA expression was associated with decreased DSS among 1,341 women (per each standard deviation increase of expression: HR 1.14, 95% CI: 1.01-1.29, P = 0.03). Pathway analyses supported prior experimental studies showing that estrogen receptor 1 () regulated expression. Canonical signaling pathways significantly differentially represented between high and low groups included those involved in inflammation and immunity.

CONCLUSION

Increased primary tumor expression was associated with decreased DSS. Pathway analyses suggested that increased was associated with endoplasmic reticular homeostasis, possibly allowing tumor cells to overcome hypoxic stress and meet the increased protein demand of tumorigenesis, thereby preventing unfolded protein response-mediated apoptosis.