Estrogen receptor alpha (ER)-negative human breast cancer cells frequently 
overexpress epidermal growth factor receptor (EGFR) and respond poorly to 
endocrine therapies. Our previous studies demonstrate that histone deacetylation 
plays a key role in ER gene silencing, and ER expression can be restored with 
histone deacetylase (HDAC) inhibitors in ER-negative human breast cancer cells. 
Whether inhibition of HDAC also alters epidermal growth factor (EGF) signaling 
pathways is not defined. Here we present evidence that reexpression of ER 
protein by a clinically available HDAC inhibitor, suberoylanilide hydroxamic 
acid (SAHA or vorinostat), is coupled with loss of EGFR in ER-negative human 
breast cancer cells. Consistent with this observation, MDA-MB-231 cells, which 
are ER-negative and overexpress EGFR, that are engineered to express ER show a 
decrease in EGFR protein expression. Down-regulation of EGFR by SAHA results 
from attenuation of its mRNA stability. We also confirm that new protein 
synthesis is required for maintaining EGFR mRNA stability. Further experiments 
indicate that a decrease in EGFR abolished EGF-initiated signaling pathways 
including phosphorylated PAK1, p38MAPK and AKT. Thus, SAHA may not only 
reactivate silenced ER, but also simultaneously deplete EGFR expression. These 
data suggest that inhibition of HDAC is a promising epigenetic therapy for 
ER-negative human breast cancer.