ribavirin restores esr1 gene expression and tamoxifen sensitivity in esr1 negative breast cancer cell lines利巴韦林恢复esr1基因表达和三苯氧胺敏感性esr1 -乳腺癌细胞系.pdfVIP

Sappok and Mahlknecht Clinical Epigenetics 2011, 3:8 /content/3/1/8 RESEARCH Open Access Ribavirin restores ESR1 gene expression and tamoxifen sensitivity in ESR1 negative breast cancer cell lines * Anne Sappok and Ulrich Mahlknecht Abstract Tumor growth is estrogen independent in approximately one-third of all breast cancers, which makes these patients unresponsive to hormonal treatment. This unresponsiveness to hormonal treatment may be explained through the absence of the estrogen receptor alpha (ESR1). The ESR1 gene re-expression through epigenetic modulators such as DNA methyltransferase inhibitors and/or histone deacetylase inhibitors restores tamoxifen sensitivity in ESR1 negative breast cancer cell lines and opens new treatment horizons in patients who were previously associated with a poor prognosis. In the study presented herein, we tested the ability of ribavirin, which shares some structural similarities with the DNA-methyltransferase inhibitor 5-azacytidine and which is widely known as an anti-viral agent in the treatment of hepatitis C, to restore ESR1 gene re-expression in ESR1 negative breast cancer cell lines. In our study we identified ribavirin to restore ESR1 gene re-expression alone and even more in combination with suberoylanilide hydroxamic acid (SAHA - up to 276 fold induction). Ribavirin and analogs could pave the way to novel translational research projects that aim to restore ESR1 gene re- expression and thus the susceptibility to tamoxifen-based endocrine treatment strategies. Keywords: epigenetic, estrogen receptor alpha, HDAC, methylation, ribavirin, SAHA Introduction express ESR1 exhibit a primary resistance to endocrine Breast cancer is the most frequent type of