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Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance

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Abstract

Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-α (ERα) promote the proliferation of breast cancer cells. Menin is a tumor suppressor encoded by Men1 that is mutated in the human-inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1); it also serves as a critical link in the recruitment of nuclear receptor-mediated transcription. Here, we show that menin expressed in breast cancer cell line MCF-7 is colocalized with ERα and functions as a direct coactivator of ER-mediated transcription in breast cancer cells. In MCF-7 cells, coexpression of menin and estrogen-response element-luciferase induced the activity of the latter in a hormone-dependent manner. Cells knocked down for ERα exhibited impaired ERE-luciferase activity induced by menin. Mammalian two-hybrid assay and GST pull-down assays indicated that menin could interact with the AF-2 domain of ERα. These results indicate that menin is a direct activator of ERα function. Tamoxifen inhibited the binding of menin to AF-2 in mammalian two-hybrid assay, but in menin-overexpressing clones, tamoxifen suppressed ERE-luciferase activity only to the levels of nontreated wild-type MCF-7. In a clinical study with 65 ER-positive breast cancer samples—all of which had been treated with tamoxifen for 2–5 years as adjuvant therapies—menin-positive tumors had a worse outcome than menin-negative ones. These indicated that menin can function as a transcriptional regulator of ERα and is a possible predictive factor for tamoxifen resistance.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe Miki-cho, Kita-gun, Kagawa, Japan

    Hitomi Imachi, Koji Murao, Hiroaki Dobashi & Toshihiko Ishida

  2. Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Mohammad M. Bhuyan

  3. Department of General Surgery, The First Clinical Hospital of Jilin University, 130021, Changchun, China

    Xueyuan Cao

  4. Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan

    Keiichi Kontani, Shoko Niki & Chisa Murazawa

  5. Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto, 602-0841, Japan

    Hiroo Nakajima

  6. Department of Medical Oncology, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan

    Norio Kohno

  7. Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Hiroko Yamashita

  8. Department of Breast and Endocrine Surgery Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Hirotaka Iwase

  9. Department of Medical Technology, School of Medicine, Course of Health Science, Tohoku University, 2-1 Seiryou-machi, Aoba-ku, Sendai, 980-8575, Japan

    Shin-ichi Hayashi

  10. Department of Cell Regulation, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, Japan

    Akira Yamauchi

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  1. Hitomi Imachi
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  2. Koji Murao
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  3. Hiroaki Dobashi
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  5. Xueyuan Cao
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Correspondence to Koji Murao.

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Imachi, H., Murao, K., Dobashi, H. et al. Menin, a product of the MENI gene, binds to estrogen receptor to enhance its activity in breast cancer cells: possibility of a novel predictive factor for tamoxifen resistance. Breast Cancer Res Treat 122, 395–407 (2010). https://doi.org/10.1007/s10549-009-0581-0

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