There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.
PurposeCholesterol lowering statins have been demonstrated to exert anti-tumoral effects on breast cancer by decreasing proliferation as measured by Ki67. The biological mechanisms behind the anti-proliferative effects remain elusive. The aim of this study was to investigate potential statin-induced effects on the central cell cycle regulators cyclin D1 and p27.Experimental designThis phase II window-of-opportunity trial (Trial registration: ClinicalTrials.gov NCT00816244, NIH) included 50 patients with primary invasive breast cancer. High-dose atorvastatin (80 mg/day) was prescribed to patients for two weeks prior to surgery. Paired paraffin embedded pre- and post-statin treatment tumor samples were analyzed using immunohistochemistry for the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the cell cycle regulators cyclin D1 and p27. Corresponding frozen tumor sample pairs were analyzed for expression of the genes coding for cyclin D1 and p27, CCND1 and CDKN1B, respectively.ResultsForty-two patients completed all study parts, and immunohistochemical evaluation of ER and PR was achievable in 30 tumor pairs, HER2 in 29 tumor pairs, cyclin D1 in 30 tumor pairs and p27 in 33 tumor pairs. The expression of ER, PR and HER2 did not change significantly following atorvastatin treatment. Cyclin D1 expression in terms of nuclear intensity was significantly decreased (P = 0.008) after statin treatment in paired tumor samples. The protein expression of the tumor suppressor p27, evaluated either as the fraction of stained tumor cells or as cytoplasmic intensity, increased significantly (P = 0.03 and P = 0.02, respectively). At the transcriptional level, no significant differences in mRNA expression were detected for cyclin D1 (CCND1) and p27 (CDKN1B). However, CCND1 expression was lower in tumors responding to atorvastatin treatment with a decrease in proliferation although not significantly (P = 0.08).ConclusionsWe have previously reported statin-induced anti-proliferative effects in breast cancer. This study suggests that cell cycle regulatory effects may contribute to these anti-proliferative effects via cyclin D1 and p27.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0486-0) contains supplementary material, which is available to authorized users.
Statins, commonly used to treat hypercholesterolemia, have also been proposed as anti-cancer agents. The identification of a predictive marker is essential. The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGcR), which is inhibited by statins, might serve as such a marker. thorough antibody validation was performed for four different HMGCR antibodies. Tumor expression of HMGCR (#AMAb90619, CL0260, Atlas Antibodies, Stockholm, Sweden) was evaluated in the Malmö Diet and cancer Study breast cancer cohort. Statin use and cause of death data were retrieved from the Swedish Prescribed Drug Register and Swedish Death Registry, respectively. Breast cancer-specific mortality (BCM) according to statin use and HMGCR expression were analyzed using Cox regression models. Three-hundred-twelve of 910 breast cancer patients were prescribed statins; 74 patients before and 238 after their breast cancer diagnosis. HMGCR expression was assessable for 656 patients; 119 showed negative, 354 weak, and 184 moderate/strong expressions. HMGCR moderate/strong expression was associated with prognostically adverse tumor characteristics as higher histological grade, high Ki67, and eR negativity. HMGcR expression was not associated with BcM. neither was statin use associated with BCM in our study. Among breast cancer patients on statins, no or weak HMGCR expression predicted favorable clinical outcome. these suggested associations need further testing in larger cohorts. Statins are medications most commonly used by patients with cardiovascular diseases and hypercholesterolemia. Cholesterol is produced by the mevalonate pathway, a metabolic pathway that also produces precursors for steroid hormones and isoprenoids 1. Statins exert competitive inhibition of the rate-limiting enzyme of the mevalonate pathway, 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), an enzyme that has been found to be differentially expressed in breast cancer tumors 2. In recent years, attention in cancer research has been drawn to the mevalonate pathway since statins have been found to exert pleiotropic intratumoral effects, suggesting a possible effectiveness in cancer. Examples of these effects are induction of apoptosis and inhibition of proliferation 3 , and immunomodulatory properties, through inhibition of Ras and Rho family GTPases 4-6 , and by decreasing the production of inflammatory cytokines and activating CD8+ T cells 7. In breast cancer, statins have also demonstrated some anti-neoplastic properties in preclinical studies of breast cancer cells 8-11. These findings are supported by epidemiological data showing protective associations between statin use and breast cancer recurrence and thus prognosis 12-14. However, biomarkers for selection of patients that may benefit from statins are needed. Previous studies have explored the correlation between tumor cell expression of HMGCR and breast cancer prognosis, as well as the association with statin treatment. One study found that high levels of HMGCR tumor expression in breast cancer was associated ...
Background: Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear.Patients and methods: We identified all Malm€ o Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users.Results: The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in nonusers. Statin use was associated with a reduced risk of breast cancer recurrence (HR adj ¼ 0.88 [95% CI: 0.82e0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HR adj ¼ 0.86 [95% CI: 0.80e0.94]) but not loco-regional recurrence (HR adj ¼ 0.97 [95% CI: 0.87e1.08]). Conclusion: In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelialmesenchymal transition.
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