Bioinformatic analysis reveals the molecular targets of tangeretin in overcoming the resistance of breast cancer to tamoxifen

Abstract

The positive outcome of tamoxifen is reduced because of the emergence of intrinsic and acquired resistance that triggers relapse and metastasis; as such, a combination therapy containing tamoxifen should be developed to improve its effectiveness in breast cancer therapy. This study was performed via an integrative bioinformatic approach to explore tangeretin, a citrus flavonoid and potential molecular target in overcoming the resistance of breast cancer to tamoxifen (TT). Six tangeretin targets, namely, AKR1C1, TNKS2, BACE1, GSK3B, EGFR, and IGF1R, were obtained, and they showed potential for application in overcoming the resistance of breast cancer to tamoxifen. The Kaplan–Meier curve revealed that the prognosis of patients with a low mRNA expression of IGF1R was significantly worse than that of the opposite group. The validation of the gene expression with GEPIA indicated that the mRNA expression levels of AKR1C1 and EGFR were significantly higher in patients with breast cancer than in the opposite group. The mRNA levels of GSK3B and EGFR were higher in recurrent breast cancer cells treated with tamoxifen than in nonrecurrent breast cancer cells. The mRNA level of TNKS2 in recurrent breast cancer cells treated with tamoxifen was lower than that in nonrecurrent breast cancer cells. This study highlighted AKR1C1, TNKS2, BACE1, GSK3B, EGFR, and IGF1R as the six potential tangeretin targets in overcoming the resistance of breast cancer to tamoxifen. However, our results should be further validated with in vitro and in vivo studies.