Abstract
We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.
Highlights
The ETS family of transcription factors regulates the expression of genes involved in normal cell development, proliferation, and differentiation[6]
Western blot analysis showed that dusp[4] expression was downregulated in Triple-negative breast cancer (TNBC) cell lines compared with non-TNBC cell lines; the opposite effect was observed for ets-1 (Fig. 1A)
Previous studies have shown that ETS family members are significantly upregulated in TNBC cells compared with other cells, whereas DUSP4 is downregulated in TNBC cells[5,24]
Summary
The ETS family of transcription factors regulates the expression of genes involved in normal cell development, proliferation, and differentiation[6]. Of ETS1 is associated with high aggressiveness and poor prognosis Consistent with this observation, ETS1 regulates the expression of important angiogenetic and extracellular matrix remodeling factors such as VEGF, MMP2, and MMP912–15. Lipophilic statins inhibit the growth and proliferation of BC cells, especially hormone receptor-negative, basal-like BC cells[21,22,23]. Based on these studies, we hypothesized that statins suppress TNBC growth by altering the expression of DUSP4 and ETS1
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