Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells
- Authors
- Kim, Jinkyoung; Lee, Jiyun; Kim, Chungyeul; Choi, Jinhyuk; Kim, Aeree
- Issue Date
- 5월-2016
- Publisher
- SAGE PUBLICATIONS LTD
- Keywords
- Tamoxifen resistance; Metformin; Breast cancer; Receptor tyrosine kinase HER2; HER3; HRG-beta 1
- Citation
- TUMOR BIOLOGY, v.37, no.5, pp.5811 - 5819
- Indexed
- SCIE
SCOPUS
- Journal Title
- TUMOR BIOLOGY
- Volume
- 37
- Number
- 5
- Start Page
- 5811
- End Page
- 5819
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/88817
- DOI
- 10.1007/s13277-015-4440-9
- ISSN
- 1010-4283
- Abstract
- Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti-tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose-and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-beta 1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-beta 1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3.
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Collections - College of Medicine > Department of Medical Science > 1. Journal Articles
- Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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