Abstract
Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been widely used to lower cholesterol and prevent cardiovascular diseases. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer, while the underlying mechanisms remain to be elucidated. Herein, we sought to investigate the effect of statins on the expression of pituitary tumor-transforming gene 1 (PTTG1), a critical gene involved in human breast cancer invasion and metastasis. Our results showed that PTTG1 is highly expressed in malignant Hs578T and MDA-MB-231 breast cancer cell lines as compared with normal or less malignant breast cancer cells. Furthermore, we found that the expression of PTTG1 was markedly suppressed by lipophilic statins, such as simvastatin, fluvastatin, mevastatin, and lovastatin, but not by hydrophilic pravastatin. In a dose and time dependent manner, simvastatin suppressed PTTG1 expression by decreasing PTTG1 mRNA stability in MDA-MB-231 cells. Both siRNA-mediated knockdown of PTTG1 expression and simvastatin treatment markedly inhibited MDA-MB-231 cell invasion, MMP-2 and MMP-9 activity, and the expression of PTTG1 downstream target genes, while ectopic expression of PTTG1 promoted cancer cell invasion, and partly reversed simvastatin-mediated inhibition of cell invasion. Mechanistically, we found that inhibition of PTTG1 expression by simvastatin was reversed by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl synthesis in regulating PTTG1 expression. Our results identified statins as novel inhibitors of PTTG1 expression in breast cancer cells and provide mechanistic insights into how simvastatin prevent breast cancer metastasis as observed in recent preclinical and clinical studies.
Highlights
Breast cancer is by far the most frequent cancer in women (23% of all cancers) and the second-most frequent cancer when both sexes are considered (Tampaki et al, 2017)
Consistent with previous report (Yoon et al, 2012), we showed that the expression of Pituitary tumor-transforming gene 1 (PTTG1) is significantly higher in malignant Hs578T and MDA-MB-231 breast cancer cell lines than that in less malignant SK-BR3 and we determined the effects of statins on PTTG1 expression in MDA-MB-231 breast cancer cell line, which expresses a high level of endogenous PTTG1
MDA-MB-231 cells were treated with four lipophilic statins and one hydrophilic statin at a concentration of 5 μmol/L for 24 h, PTTG1 expression was determined by western blot
Summary
Breast cancer is by far the most frequent cancer in women (23% of all cancers) and the second-most frequent cancer when both sexes are considered (Tampaki et al, 2017). Invasion of cancer cells into surrounding tissue and the vasculature is an initial step during tumor metastasis and considered as a clinical challenge of breast cancer treatment (Hainaut and Plymoth, 2013; Chou et al, 2016; Butti et al, 2019). Simvastatin, as one of the most commonly used statins, has demonstrated significant beneficial effects in reducing breast cancer metastasis and recurrence (Ahern et al, 2011; Chae et al, 2011; Clendening and Penn, 2012; Beckwitt et al, 2018b; Li et al, 2019). The underlying mechanisms by which statins inhibit tumor cell metastasis are not fully understood, several studies have implicated the Rho/ROCK pathway, which is inhibited by statin treatment, as a key mechanism involved in regulation of cancer survival, proliferation, and invasion by statins (Denoyelle et al, 2001; Demierre et al, 2005)
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