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Recombinant viral protein VP1 suppresses HER-2 expression and migration/metastasis of breast cancer

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Breast Cancer Research and Treatment Aims and scope Submit manuscript

An Erratum to this article was published on 15 February 2016

Abstract

Breast cancer is one of the most common cancers in women worldwide and metastasis is the major cause of breast cancer death. Development of new therapeutic agents for inhibiting breast cancer metastasis is therefore an urgent need. We previously demonstrated that recombinant DNA-derived viral capsid protein VP1 (rVP1) of foot-and-mouth disease virus-induced apoptosis of MCF-7 breast cancer cells in vitro. Here, we investigated whether rVP1 exhibits any inhibitory effects on migration/metastasis and human epidermal growth factor receptor 2 (HER-2), a well-known biomarker for poor prognosis of breast cancer. The effects of rVP1 on cancer cell migration/invasion and metastasis were evaluated using Transwell migration assay and animal cancer models of metastasis. Western blotting, RT-PCR, flow cytometry, immunohistochemistry, and immunofluorescence staining techniques were used to investigate the effects of rVP1 on HER-2 and signal transduction mediators. Non-cytotoxic concentrations of rVP1-induced mesenchymal-epithelial transition and significantly suppressed AP-2α and HER-2 expression as well as the migration and invasion of a variety of breast cancer cell lines in a β1-integrin-dependent manner in vitro. Gross and histopathologic examinations showed that rVP1 also suppressed metastasis of several breast cancer cell lines, including HER-2-overexpressing SK-BR-3 and BT-474 cells to lung, liver, or peripheral lymph node in orthotopic allograft/xenograft murine models. In addition, rVP1 significantly prolonged survival in breast cancer-bearing mice. Notably, no apparent side effects of rVP1 were detected, as shown by normal complete blood count levels and serum biochemistry profiles, including AST, ALT, BUN, and creatine. This study demonstrates that rVP1 suppresses the migration, invasion, and metastasis of breast cancer cells via binding to β1 integrin receptor and down-regulation of AP-2α and HER-2 expression. The effectiveness of rVP1 on inhibiting migration/metastasis of breast cancer and HER-2 expression suggests that it may be suitable for serving as potential therapeutics for metastatic breast cancer particularly HER-2-overexpressing cancer.

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Abbreviations

rVP1:

Recombinant viral capsid protein 1

FMDV:

Foot-and-mouth disease virus

MET:

Mesenchymal-to-epithelial transition

HER-2:

Human epidermal growth factor receptor 2

AP-2α:

Activator protein-2α

PMMEC:

Primary mouse mammary epithelial cells

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Acknowledgments

We thank Dr. Michael Hsiao (Genomics Research Center, Academia Sinica, Taiwan) for kindly providing the H184B5F5, BT-474, and SK-BR-3 cell lines. We also thank the Taiwan Mouse Clinic which is funded by the National Research Program for Genomic Medicine (NRPGM) and the National Science Council (NSC) of Taiwan, and the National Laboratory Animal Center, Taipei, Taiwan for technical support with the complete blood count (CBC) and serum biochemistry assay; and Miss Miranda Loney, Institute of Molecular Biology and Agricultural Biotechnology Research Center English Editor’s Office, Academia Sinica, Taiwan, for English editorial assistance. This work was supported by the NSC, Taiwan (grant NSC 99-2313-B-001-004-MY3 to Shu-Mei Liang), and Academia Sinica (to Shu-Mei Liang and Chi-Ming Liang).

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Agricultural Biotechnology Research Center, Academia Sinica, Taipei, 115, Taiwan

    Shao-Wen Hung, Ching-Feng Chiu, Tai-An Chen, Chiao-Li Chu, Lie-Fen Shyur & Shu-Mei Liang

  2. Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan

    Ching-Feng Chiu & Shu-Mei Liang

  3. Graduate Institute of Sports Science, National Taiwan Sport University, Taoyuan, 333, Taiwan

    Chi-Chang Huang

  4. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Chi-Ming Liang & Shu-Mei Liang

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  1. Shao-Wen Hung
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An erratum to this article is available at http://dx.doi.org/10.1007/s10549-016-3711-5.

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Supplementary Fig. 1

rVP1 at concentration below 0.2 μM does not decrease cell viability and induce apoptosis of breast cancer cells. Breast cancer cell lines of mouse (TS/A and 4T1) and human (MDA-MB-231 and MCF-7) as well as primary mouse mammary epithelial cells (PMMEC) were treated with various serial two-fold diluted concentrations of rVP1 (0.1 μM-1.6 μM) at 37 °C for 24 h in serum-free medium. Cell viability was determined using MTT assay. Results were reproduced in three independent experiments. Data represent mean ± SD (n = 4). (TIF 503 KB)

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Hung, SW., Chiu, CF., Chen, TA. et al. Recombinant viral protein VP1 suppresses HER-2 expression and migration/metastasis of breast cancer. Breast Cancer Res Treat 136, 89–105 (2012). https://doi.org/10.1007/s10549-012-2238-7

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