RNA helicase DDX20 as a surrogate marker of statin activity in invasive breast cancer

OBJECTIVE To evaluate if RNA helicase DDX20,highly expressed in triple negative breast cancer(TNBC)cells,could serve as a surrogate marker for simvastatin treatment response.METHODS We first assessed correlation between 17 mevalonate pathway-related genes and expression of DDX20 in a cohort of 1325 breast cancer tumors.TNBC cells,MDA-MB-231,were then treated with simvastatin and mevalonate pathway intermediates to assess the alteration in DDX20 expression.In the mouse model,MDA-MB-231 cells were injected to tail veins of mice,groups of 8mice each were injected intraperioneally with vehicle or simvastatin 25mg·kg-1 3times a week for 6weeks.The number of metastatic colonies formed was quantified and immunohistochemical(IHC)staining of DDX20 was carried out in the lung tissues.RESULTS Among the 17 genes evaluated,positive correlation with DDX20 expression was observed in eight of them,with HMGCR having the highest correlation.Our in vitro experiments show exposure of breast cancer cells to simvastatin lead to a Rho-dependent decrease in gene expression of DDX20,leading to decreased tumor proliferation in a mevalonate pathway-dependent manner.Conversely,ectopic overexpression of DDX20 significantly abrogated the anti-metastatic activity of simvastatin.A similar observation is seen in the mouse model,where simvastatin-injected mice show significantly fewer visible lung metastases compared to placebo-fed mice.IHC staining on these lung tissues showed decreased DDX20 expression in simvastatin-injected group,corroborating our observations in vitro.CONCLUSION DDX20 is a potential surrogate marker for simvastatin treatment response in breast cancer and a long term implication of our findings is the possibility of an effective combinatorial therapeutic intervention using statins(to suppress DDX20 gene expression)and a suitable firstline agent″for the kill″of invasive breast cancer.