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Inhibition of cyclin D1 expression by androgen receptor in breast cancer cells: identification of a novel androgen response element
Author(s) -
Lanzino Marilena,
Sisci Diego,
Morelli Catia,
Catalano Stefania,
Casaburi Ivan,
Capparelli Claudia,
Avena Paola,
Andò Sebastiano
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.566.3
Subject(s) - cyclin d1 , androgen receptor , cancer research , cyclin d , biology , cyclin a2 , cyclin b , microbiology and biotechnology , chemistry , cell cycle , gene , cancer , genetics , prostate cancer
Cyclin D1 gene ( CCND1 ) is a critical mitogen‐regulated cell cycle control element whose transcriptional modulation play a crucial role in breast cancer growth and progression. Here we demonstrated that the non‐aromatizable androgen receptor (AR) ligand, 5‐alpha‐dihydrotestosterone (DHT), inhibits endogenous CCND1 expression, as evidenced by reduction of cyclin D1 mRNA and protein levels, and decrease of CCND1 ‐promoter activity, in MCF‐7 cells. The DHT‐dependent inhibition of CCND1 gene activity requires the involvement and the integrity of the AR DNA Binding Domain. Site directed mutagenesis, DAPA, EMSA and ChIP analyses indicate that this inhibitory effect is ligand‐dependent and it is mediated by direct binding of AR to an Androgen Response Element ( CCND1 ‐ARE), located in the cyclin D1 proximal promoter. Identification of this CCND1 ‐ARE allows to define cyclin D1 as a specific androgen target gene in breast. AR‐mediated repression of the cyclin D1 gene involves the recruitment of the atypical orphan nuclear receptor DAX1 as a component of a multiprotein repressor complex also embracing the participation of Histone Deacetylase 1. In conclusion, we identified a novel AR‐mediated mechanism able to negatively regulate cyclin D1, contributing to explain the molecular basis of mechanisms through which androgens exert their inhibitory role on the proliferation of breast cancer cells.