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

Autor: Akira Yamauchi, Toshihiko Ishida, Shin Ichi Hayashi, Chisa Murazawa, Xueyuan Cao, Norio Kohno, Hitomi Imachi, Hiroo Nakajima, Hirotaka Iwase, Hiroko Yamashita, Mohammad M. Bhuyan, Keiichi Kontani, Hiroaki Dobashi, Shoko Niki, Koji Murao
Rok vydání: 2009
Předmět:
Cancer Research
Time Factors
endocrine system diseases
Estrogen receptor
Kaplan-Meier Estimate
Chlorocebus aethiops
Protein Interaction Mapping
Promoter Regions
Genetic
skin and connective tissue diseases
Estradiol
Estrogen Antagonists
Nuclear Proteins
Middle Aged
Prognosis
Gene Expression Regulation
Neoplastic
Oncology
Chemotherapy
Adjuvant
COS Cells
Female
RNA Interference
Breast disease
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Transcriptional Activation
congenital
hereditary
and neonatal diseases and abnormalities
endocrine system
medicine.medical_specialty
Recombinant Fusion Proteins
Breast Neoplasms
Biology
Transfection
Disease-Free Survival
Cell Line
Tumor
Proto-Oncogene Proteins
Two-Hybrid System Techniques
Internal medicine
Coactivator
medicine
Animals
Humans
MEN1
Neoplasm Staging
Binding Sites
Estrogen Receptor alpha
Cancer
medicine.disease
Antiestrogen
Tamoxifen
Endocrinology
Drug Resistance
Neoplasm
Cancer research
Estrogen receptor alpha
Zdroj: Breast Cancer Research and Treatment. 122:395-407
ISSN: 1573-7217
0167-6806
Popis: 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.
Databáze: OpenAIRE
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