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.
Multiple coactivator and corepressor complexes play an important role in endocrine processes and breast cancer; in particular, estrogen and estrogen receptor-alpha (ERalpha) 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 ERalpha 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 ERalpha 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 ERalpha. These results indicate that menin is a direct activator of ERalpha 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 ERalpha and is a possible predictive factor for tamoxifen resistance.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe Miki-cho, Kita-gun, Kagawa, Japan.
Hitomi
H
Imachi
Koji
K
Murao
Hiroaki
H
Dobashi
Mohammad M
MM
Bhuyan
Xueyuan
X
Cao
Keiichi
K
Kontani
Shoko
S
Niki
Chisa
C
Murazawa
Hiroo
H
Nakajima
Norio
N
Kohno
Hiroko
H
Yamashita
Hirotaka
H
Iwase
Shin-ichi
S
Hayashi
Toshihiko
T
Ishida
Akira
A
Yamauchi
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D002522:Chlorocebus aethiops; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C105373:MEN1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D004958:Estradiol