Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a

Abstract

Purpose We previously reported using statins was correlated with improved metastasis free survival in aggressive breast cancer. The purpose of this study was to examine the effect of statins on metastatic colonization by triple negative breast cancer (TNBC) cells. Experimental Design TNBC cell lines were treated with simvastatin and then studied for cell cycle progression and proliferation in vitro, and metastasis formation in vivo, following injection of statin-treated cells. Reverse-phase protein assay (RPPA) analysis was performed on statin-treated and control breast cancer cells. RNA interference targeting FOXO3a was used to measure the impact of simvastatin on FOXO3a-expressing cells. The prognostic value of FOXO3a mRNA expression was examined in 8 public breast cancer gene expression data sets including 1,479 patients. Results Simvastatin increased G1/S phase arrest of the cell cycle and inhibited both proliferation and migration of TNBC cells in vitro. In vitro pretreatment and in vivo treatment with simvastatin reduced metastases. Phosphorylated FOXO3a was downregulated after simvastatin treatment in (RPPA) analysis. Ectopic expression of FOXO3a enhanced mammosphere formation and migratory capacity in vitro. Knockdown of FOXO3a attenuated the effect of simvastatin on mammosphere formation and migration. Analysis of public gene expression data demonstrates FOXO3a mRNA downregulation was independently associated with shorter metastasis-free survival in all breast cancers, as well as in TNBC breast cancers. Conclusions Simvastatin inhibits in vitro endpoints associated with metastasis through a FOXO3a mechanism and reduced metastasis formation in vivo. FOXO3a expression is prognostic for metastasis formation in patient data. Further investigation of simvastatin as a cancer therapy is warranted.

Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer

“…inactivate FOXO3A and its target, estrogen receptor-a, in turn removing a block on c-Rel to mediate mammary tumorigenesis (32). Interestingly, our team showed that simvastatin, which promotes radiosensitivity of IBC cells (33), prevents breast cancer metastasis via stabilization of FOXO3A (34). This work suggests the promise for IBC of combination therapeutic approaches that include drugs that educate the tumor microenvironment in patients with indication of M2 macrophage activation.…”

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…To date, many drugs associated with obesity such as lipid-lowering (statins) or antidiabetic drugs (metformin) have been used in cancer treatment with good effects (Brown, 2007;De Queiroz et al, 2015;Hager et al, 2006;Hanai et al, 2012;Wang et al, 2014). Appropriately, it has been demonstrated that both statins and metformin are able to increase the activity of FOXO3 (De Queiroz et al, 2015;Wolfe et al, 2015), whereas metformin is also able to inhibit the expression of FOXM1 . Collectively, these observations advocate further that targeting lipid metabolism in conjunction with the FOXO3-FOXM1 axis maybe a viable strategy for tackling cancer development, progression and drug resistance.…”

Impact of Statin Use on Outcomes in Triple Negative Breast Cancer

“…Numerous studies have implicated cholesterol regulation in both the risk and progression of breast cancer 6 . Our lab and others have shown that cholesterol regulation can influence pre-clinical models of triple negative breast cancer through a PI3K/FOXO3a pathway, affecting stem cells and metastases 7 - 9 .…”