Ribavirin restores ESR1 gene expression and tamoxifen sensitivity in ESR1 negative breast cancer cell lines

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.Breast cancer is the most frequent type of cancer in women in the Western world and the second leading cause of cancer death. Approximately one in 8 women living in the USA today is being diagnosed with breast cancer at some point during her lifetime [1].In the clinic, the estrogen receptor (ESR) and more precisely the estrogen receptor α (ESR1) is an important prognostic disease marker [2]. Approximately two-thirds of breast cancers are ESR1-positive.The binding of estrogen to the ESR1 is not only a key regulator for the physiological growth and differentiation of the mammary gland, it is also a key element in the malignant progression of breast cancer, i.e. the growth of ESR1 expressed breast cancer cells is stimulated by estrogen, which in turn makes it accessible to endocrine treatment strategies, while breast cancers that do not express ESR1 exhibit a primary resistance to endocrine treatment [3,4]. Therefore, the presence of ESR1 correlates with increased disease-free survival and a better prognosis when compared to ESR1-negative breast cancers [5]. While at the time of diagnosis up to one-third of breast cancers are ESR1 negative, quite a few cancers that are initially ESR1 positive lose the ESR1 during the course of tumor progression and are therefore no longer respo