Lovastatin lowers the risk of breast cancer: a population-based study using logistic regression with a random effects model

Our population data revealed a potential protective effect of lovastatin against breast cancer in Taiwanese people. Differences in breast cancer incidence between different ethnicities cannot be ignored. From 2004 to 2008, the incidence rates of female breast cancer in the United States ranged from 84.9 to 125.4 cases per 100,000 women, with the lowest mortality from breast cancer observed in Asian Americans and Pacific Islanders (DeSantis et al. 2011). The association between statin use and breast cancer risk should therefore be evaluated in distinct ethnic populations.

In this study, we found that lovastatin produced a statistically significant protective effect against breast cancer after adjusting for potential confounding factors. Atorvastatin exhibited only a protective tendency against breast cancer. We proposed a logistic regression model coupled with a random urbanization effects model to take into account the potential bias caused by random urbanization, and we used the CCI to evaluate potential comorbidities. We also adjusted for the effect of urbanization, because nutrition and lifestyle are related to breast cancer incidence (Chajes and Romieu 2014).

Our study analyzed the use of five statins based on a large population database of Taiwanese people, and found that lovastatin showed a protective effect against breast cancer. In contrast to the negative findings of other current studies looking at statins and breast cancer risk, the large sample size of our study enhanced the results and made possible the subgroup analysis of each statin. Because of the different chemical properties of lipophilic and hydrophilic statins, most previous studies classified statins into these two groups. However, to prove an association between statin use and the risk of breast cancer requires each statin to be examined individually.

Several studies have suggested reasons to explain why statins are potential chemopreventive agents. One study proposed that statins reduce the production of substances that are crucial for correct localization and translocation to cell membranes; in other words, statins can inhibit molecular signaling pathways (Denoyelle et al. 2001).

In 1990, lovastatin and pravastatin were introduced to the Taiwanese market as the first 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) (Li et al. 2010). The use of statins in Taiwan rapidly increased with the increasing need to prevent coronary heart disease. Most patients who take statins are likely to be long-term users because of their preventive effects, the main effect being to reduce plasma cholesterol levels by inhibiting a rate-limiting step in the cholesterol synthesis pathway. Statins interrupt the catalysis from HMG-CoA to mevalonate. The reduction of mevalonate contributes to a reduction of geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). These compounds have an important function in molecular signaling pathways in cancer cells. Increasing evidence has revealed that statins have another valuable effect in preventing cancer (Boudreau et al. 2007; Jafari et al. 2013; Ahern et al. 2014). Various laboratory studies have demonstrated the statin-induced apoptosis of cancer cells, including breast cancer cells, with increasing evidence accumulating on the mechanism underlying this (Campbell et al. 2006; Corsini et al. 1995; Dimitroulakos et al. 2001; Niknejad et al. 2007; Woditschka et al. 2010; Ma et al. 2012; Niknejad et al. 2014). Preclinical findings favor the possibility that lovastatin exerts anticancer effects, including effects against breast cancer. However, despite numerous epidemiological studies, no consensus has been established regarding the relationship between statin use and breast cancer risk (Undela et al. 2012). A population-based, case–control study by Boudreau et al. involving 1982 postmenopausal women did not support an association between statin use and breast cancer risk. However, they suggested that long-term statin use (for longer than 5 years) was associated with a slight decrease in the risk of breast cancer (Boudreau et al. 2004). Recently, a population-based case–control study using a nationwide cohort was conducted in Taiwan and found no evidence of an association between statin use and breast cancer (Chan et al. 2014). That study included only patients who were aged at least 50 years, which was a narrower range of age compared to our study. Furthermore, it did not analyze each statin individually. In contrast, Pocobelli et al. reported that patients who used fluvastatin (and no other lipophilic statin) for less than 5 years exhibited a lower risk of breast cancer than did nonusers (Pocobelli et al. 2008). The Women’s Health Initiative cohort study conducted by Cauley et al. reported that users of lipophilic statins (e.g., lovastatin, simvastatin, and atorvastatin) exhibited an 18% lower breast cancer incidence than did nonusers (Cauley et al. 2006). However, after the same cohort was followed up, it was concluded that lipophilic statin users exhibited no significant reductions in breast cancer risk (Desai et al. 2013). Woditschka et al. investigated the association between the risk of specific breast cancer subtypes and lipophilic statin use, and concluded that lipophilic statin users exhibited no reduction in the risk of any breast cancer subtype (Woditschka et al. 2010). Kwan et al. reported that the risk of breast cancer recurrence in all statin users decreased with increasing duration of use after diagnosis (Kwan et al. 2008). In addition, the use of lipophilic statins, particularly simvastatin, was associated with significantly reduced breast cancer recurrence rates in a Danish nationwide cohort study (Ahern et al. 2011). In contrast, one case–control study observed a significantly increased risk of breast cancer in postmenopausal obese women who used lipophilic statins (Eaton et al. 2009). The hypothesis that there is no association between statin use and breast cancer risk has been supported by most observational and epidemiological studies, including three meta-analyses (Undela et al. 2012; Bonovas et al. 2005; Dale et al. 2006). However, organ specificities for the pleomorphic and cholesterol-lowering effects have been observed, although the mechanism for this organ specificity is unknown.

Lovastatin, the first statin isolated (in 1979), has been used clinically for more than two decades and its lipid-lowering and other pleomorphic effects have been thoroughly studied (Corsini et al. 1995; Boudreau et al. 2004). Meanwhile, the effect of lovastatin on apoptosis has been carefully investigated (Corsini et al. 1995). One study examined 59 cell lines for sensitivity to lovastatin-induced apoptosis, and demonstrated that it was tumor specific (Dimitroulakos et al. 2001). The mechanism of lovastatin-induced apoptosis has been reported in several studies. Laboratory studies using mouse models of breast cancer demonstrated that lovastatin inhibits tumor growth and metastasis (Woditschka et al. 2010). Niknejad et al. identified transcription factors that play a crucial role in lovastatin-induced apoptosis in head and neck squamous cell carcinoma cell lines (Niknejad et al. 2007), and multiple stress pathways were found to regulate the cytotoxic effects of lovastatin in squamous cell carcinoma cell lines (Ma et al. 2012). Another study reported that certain substances enhanced lovastatin-induced apoptosis (Niknejad et al. 2014). It has been shown that lovastatin inhibited cell invasion and cell proliferation in breast cancer cell lines (Kang et al. 2009; Klawitter et al. 2010). Thus, preclinical findings support the possibility that lovastatin exerts anticancer effects, including effects against breast cancer cells. However, it should be taken into consideration that cancer cell lines in preclinical studies are exposed to high concentrations of lovastatin, typically ten to one hundred times higher than therapeutic levels (Cho et al. 2011). Organ specificity for lovastatin’s cholesterol-lowering effect has been reported by several studies, and statins have been described as exhibiting organ specificity. Lovastatin inhibits cholesterol synthesis in several organs, whereas pravastatin inhibits cholesterol synthesis mainly in the liver and ileum (Koga et al. 1990; Tsujita et al. 1986). This may explain why each statin exhibits different characteristics in terms of their pleomorphic effects.