Zhou Qun, Shaw Patrick G, Davidson Nancy E
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans Street, CRBI Room 144, Baltimore, MD 21231, USA.
Breast Cancer Res Treat. 2009 Sep;117(2):443-51. doi: 10.1007/s10549-008-0148-5. Epub 2008 Aug 6.
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.
雌激素受体α（ER）阴性的人乳腺癌细胞经常过度表达表皮生长因子受体（EGFR），并且对内分泌治疗反应不佳。我们之前的研究表明，组蛋白去乙酰化在ER基因沉默中起关键作用，并且在ER阴性的人乳腺癌细胞中，组蛋白去乙酰化酶（HDAC）抑制剂可以恢复ER的表达。HDAC的抑制是否也会改变表皮生长因子（EGF）信号通路尚不清楚。在此，我们提供证据表明，临床上可用的HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA或伏立诺他）使ER蛋白重新表达，这与ER阴性的人乳腺癌细胞中EGFR的缺失相关。与此观察结果一致，ER阴性且过度表达EGFR的MDA-MB-231细胞经基因工程改造表达ER后，EGFR蛋白表达降低。SAHA导致的EGFR下调是其mRNA稳定性减弱所致。我们还证实，维持EGFR mRNA稳定性需要新的蛋白质合成。进一步的实验表明，EGFR的减少消除了包括磷酸化PAK1、p38MAPK和AKT在内的EGF启动的信号通路。因此，SAHA不仅可能重新激活沉默的ER，还可能同时降低EGFR的表达。这些数据表明，抑制HDAC是一种有前景的针对ER阴性人乳腺癌的表观遗传疗法。
