Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor alpha.
The interaction between 17beta-estradiol and estrogen receptor alpha (ER-alpha) plays an important role in breast carcinogenesis and breast cancer treatment. ER-alpha is a critical growth regulatory gene in breast cancer and its expression level is tightly linked to the prognosis and treatment outcomes of breast cancer patients. Loss of ER-alpha expression in breast epithelial cells is critical for breast cancer progression. The underlying molecular mechanisms for this loss, however, are poorly defined. Histone deacetylases (HDACs) are implicated in the alteration of chromatin assembly and tumorigenesis. We show that histone deacetylase 1 (HDAC1) interacts with ER-alpha in vitro and in vivo and suppresses ER-alpha transcription activity. The interaction of HDAC1 with ER-alpha was mediated by the AF-2 and DBD domains of ER-alpha. We observed an endogenous interaction of HDAC1 with ER-alpha in breast cancer cells, which was decreased in the presence of estrogen. Interestingly, overexpression of HDAC1 in stable transfected MCF-7 clones induced loss of ER-alpha and significantly increased cell proliferation and colony formation, as compared to the control MCF-7 cells, whereas treatment of stable MCF-7 clones with the HDAC specific inhibitor trichostatin A (TSA) induced re-expression of ER-alpha mRNA and protein. Our findings strongly suggest that HDAC1 affects breast cancer progression by promoting cellular proliferation in association with a reduction in both ER-alpha protein expression and transcriptional activity. Thus, HDAC1 may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers.
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D018450:Disease Progression; D047628:Estrogen Receptor alpha; D005260:Female; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000032:analysis / Q000502:physiology*; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; D006877:Hydroxamic Acids; D011960:Receptors, Estrogen; C012589:trichostatin A; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases