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.