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

Hitomi Imachi, Koji Murao, Hiroaki Dobashi, Mohammad M. Bhuyan, Xueyuan Cao, Keiichi Kontani, Shoko Niki, Chisa Murazawa, Hiroo Nakajima, Norio Kohno, Hiroko Yamashita, Hirotaka Iwase, Shin Ichi Hayashi, Toshihiko Ishida, Akira Yamauchi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptorα (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.

Original languageEnglish
Pages (from-to)395-407
Number of pages13
JournalBreast Cancer Research and Treatment
Volume122
Issue number2
DOIs
Publication statusPublished - 2010 Jul

Keywords

  • Breast cancer
  • Estrogen receptor
  • Menin
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Imachi, H., Murao, K., Dobashi, H., Bhuyan, M. M., Cao, X., Kontani, K., Niki, S., Murazawa, C., Nakajima, H., Kohno, N., Yamashita, H., Iwase, H., Hayashi, S. I., Ishida, T., & Yamauchi, A. (2010). 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 Research and Treatment, 122(2), 395-407. https://doi.org/10.1007/s10549-009-0581-0