Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial

Abstract

Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment.

Statins are potential anticancerous agents (Review)

“…A pre-operative study in primary invasive breast cancer patients investigated atorvastatin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response. Results of that study suggest HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an antiproliferative effect in HMGCR-positive tumors (20). Furthermore, fluvastatin reduced tumor proliferation and increased apoptotic activity in high-grade, stage 0/1 breast cancer in invasive breast cancer patients (21).…”

Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer

“…Cohort 1 This cohort comprises 42 women with primary breast cancer, who were enrolled in a pre-surgical window-of-opportunity trial conducted at the Skåne University Hospital in Lund, Sweden, evaluating the effect of two weeks of high-dose atorvastatin on breast cancer proliferation (Bjarnadottir et al 2013). The study was registered at ClinicalTrials.gov (#NCT00816244) December 30, 2008.…”

“…Serum samples collected before and after the completion of two weeks treatment with high-dose atorvastatin (80 mg daily) were analyzed for total cholesterol, LDL cholesterol and high-density lipoprotein (HDL) cholesterol concentrations according to standard clinical diagnostic procedures at Skåne University Hospital, Lund, Sweden. Other tumor pathological factors have been previously assessed (Supplementary Table 1 and Bjarnadottir et al (2013)). Serum 27HC and tumorspecific CYP27A1 expression were determined by mass spectrometry and immunohistochemistry, respectively.…”

Statin use, Candidate Mevalonate Pathway Biomarkers, and Colon Cancer Survival in a Population-Based Cohort Study

“…Further exploration in additional molecular pathological epidemiology cohorts should be considered, as the complete-case subgroup analysis results are in line with an in vivo breast cancer study which suggests that statins may have an anti-proliferative effect in tumours that overexpress HMGCR. (Bjarnadottir et al, 2013) Overexpression of HMGCR has been proposed to be prognostic in a number of malignancies including breast (Borgquist et al, 2008;Brennan et al, 2011) and epithelial ovarian cancer. (Brennan et al, 2010) However, a recent population-based breast cancer cohort study failed to demonstrate that overexpression of HMGCR was associated with better survival.…”

“…(Bjarnadottir et al, 2013) Finally, RAS signaling may be inhibited by statin-induced depletion of downstream isoprenoids required for posttranslational prenylation of small GTPases 7 like ras and rho. (Bardou et al, 2010;Ng et al, 2011;Thurnher et al, 2012) Prenylation of k-ras makes the protein lipophilic and ensures translocation to the cell membrane where it can exert its proliferative effects.…”