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Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells

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Tumor Biology

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)-β1-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-β1 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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Acknowledgments

This research was supported by a grant of the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (MOHW), Republic of Korea (grant number: A120392).

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    1. Department of Pathology, Korea University Guro Hospital, #148 Gurodong-ro, Guro-gu, Seoul, 152-703, South Korea

      Jinkyoung Kim, Chungyeul Kim, Jinhyuk Choi & Aeree Kim

    2. Department of Pathology, College of Medicine, Korea University, #73 Inchon-ro, Seongbuk-gu, Seoul, 136-705, South Korea

      Jiyun Lee

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    Jinkyoung Kim, Jiyun Lee and Chungyeul Kim contributed equally to this work.

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    Kim, J., Lee, J., Kim, C. et al. Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells. Tumor Biol. 37, 5811–5819 (2016). https://doi.org/10.1007/s13277-015-4440-9

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