Association of the m6A reader IGF2BP3 with tumor progression and brain‐specific metastasis in breast cancer

Abstract Background This study aimed to determine the role of insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), an N 6 ‐methyladinosine reader, in the progression and distant metastasis of breast cancer. Methods IGF2BP3 expression was assessed in 152 pairs of breast cancer and adjacent normal tissue (ANT) by real‐time quantitative polymerase chain reaction and in 561 cases of breast cancer and 163 cases of ANT by immunohistochemistry. Survival curves were estimated using the Kaplan–Meier method and then compared statistically using the log‐rank test. The prognostic role of IGF2BP3 was determined by Cox regression analysis. Results Analysis of public gene data sets revealed that IGF2PB3 predicted distant metastasis in breast cancer and was highly correlated with brain metastasis. In the clinical retrospective cohort, the positive rate of IGF2BP3 increased gradually with breast cancer progression. Positive IGF2BP3 expression was related to poor distant metastasis‐free survival (DMFS, p = .030) and Cox regression analysis identified IGF2BP3 as an independent risk factor for DMFS (hazard ratio, 1.876; 95% confidence interval, 1.128–3.159; p = .019). Positive IGF2BP3 expression was markedly related to breast cancer brain metastasis ( p = .011) but not to lung and bone metastasis. Moreover, patients with IGF2BP3‐positive brain metastasis had lower survival than patients with IGF2BP3‐negative brain metastasis ( p = .041). Gene expression profiling results indicated that high IGF2BP3 expression was associated with the PD‐1 checkpoint pathway, HER2‐HER3 signaling, and epithelial–mesenchymal transition. Conclusions IGF2BP3 may serve as a novel predictive biomarker and a potential therapeutic target for breast cancer brain metastasis, which warrants further investigation. Plain Language Summary As an m 6 A reader, IGF2BP3 is dysregulated and implicated in various cancers but its role in breast cancer has not been fully clarified. In this study, we found that IGF2BP3 was upregulated in breast cancer and IGF2BP3 expression increased gradually during breast cancer progression. IGF2BP3 expression exerted no effect on the overall survival and breast cancer–specific survival of breast cancer patients; however, IGF2BP3‐positive patients were more likely to develop distant metastasis than IGF2BP3‐negative patients. In addition, IGF2BP3 was associated with brain‐specific metastasis in breast cancer patients. These findings warrant further investigation because they provide a rationale for novel predictive or therapeutic approaches.