Quercetin Blocks the Aggressive Phenotype of Triple Negative Breast Cancer by Inhibiting IGF1/IGF1R-Mediated EMT Program

Wei-Jen Chen ^a,b,*, Jie-Heng Tsai ^c, Li-Sung Hsu ^d,e, Chih-Li Lin ^e,f, Hui-Mei Hong ^a,b, Min-Hsiung Pan ^g,h,i,**

a Department of Biomedical Sciences, Chung Shan Medical University, Taichung, 402, Taiwan

b Department of Medical Research, Chung Shan Medical University Hospital, Taichung, 402, Taiwan

c School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei, 110, Taiwan

d Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 402, Taiwan

e Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, 402, Taiwan

f Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan

g Institute of Food Science and Technology, National Taiwan University, Taipei, 106, Taiwan

h Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan

i Department of Health and Nutrition Biotechnology, Asia University, Taichung, 41354, Taiwan

The cancer-preventive activities of quercetin have been extensively studied in invasive breast cancer; however, the role of quercetin on triple-negative breast cancer (TNBC) with overexpression of insulin-like growth factor-1 receptor (IGF1R) has not been resolved. In this article, we demonstrated that quercetin inhibited the activation of IGF1R and its downstream kinases Akt and Erk1/2 in a dose-dependent manner in human MDA-MB-231 breast cancer cells (TNBC cell line). Related to this, quercetin markedly suppressed the metastatic phenotype and epithelialemesenchymal transition (EMT) of MDA-MB-231 cells by inhibiting the expression of EMT transcription factors Snail and Slug. Quercetin also increased the secretion of IGF-binding protein-3 in the conditioned medium of MDA-MB-231 cells while reducing the secretion of IGF1; thus, quercetin interrupted the autocrine or paracrine loop of IGF1 signaling. In xenograft mouse models, the administration of quercetin blocked the growth of MDA-MB-231 tumor xenografts and their lung metastasis, accompanied by the inactivation of IGF1R and the downregulation of the expression of Snail, Slug, and mesenchymal markers fibronectin and vimentin. These results suggest that quercetin has cancer-preventive value for TNBC by inhibiting IGF1/IGF1R signaling and preventing the consequent EMT and metastasis of TNBC.

Keywords: Quercetin, MDA-MB-231 cells, IGF1R, IGF1, EMT

https://doi.org/10.38212/2224-6614.3090

(https://www.jfda-online.com/journal/vol29/iss1/8)