Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

Ahern, Thomas P.; Pedersen, Lars; Tarp, Maja; Cronin‐Fenton, Deirdre; Garne, Jens Peter; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.

doi:10.1093/jnci/djr291

Cited by 325 publications

(332 citation statements)

References 49 publications

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“…Statin users have been reported to have reductions of cancer incidence by up to about 50%, 74 --79 lower grade and stage of tumor, 80 and a decreased risk of recurrence. 81,82 By contrast, other studies found no association between statin use and cancer risk. 83 --85 These latter studies, however, have also been criticized for short follow-up times, and lack of consideration for the type of statin as well tumor subtype.…”

Section: Mid 1970smentioning

confidence: 89%

Targeting tumor cell metabolism with statins

2012

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The mevalonate pathway is a core biochemical process, crucial for the generation of cholesterol and other key metabolic end products. The rate-limiting enzyme of the mevalonate pathway, hydroxymethylglutaryl coenzyme A reductase (HMGCR), is safely and effectively targeted by the statin family of inhibitors to treat hypercholesterolemia. The anticancer activity of statins has also been widely reported, yet the tumor-selective mechanisms that mediate these antiproliferative effects remain largely unclear. The importance of altered metabolism in the context of tumorigenesis has received renewed attention as metabolic changes entwined with the molecular hallmarks of cancer have been elucidated. Although several metabolic pathways have been linked to cancer progression and etiology, it was only recently that HMGCR and the mevalonate pathway were also shown to have a distinct role in cellular transformation. In this review, we chart the historical progression of statins from cholesterol-lowering blockbusters to anticancer agents with imminent potential, and further discuss an emerging role for HMGCR and the mevalonate pathway in the metabolic reprogramming of cancer.

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Section: Mid 1970smentioning

confidence: 89%

Targeting tumor cell metabolism with statins

2012

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“…Based on these observations, GGTI treatment appears as a promising anti-CSC therapy. The use of statins, which inhibit MVA metabolism, reduces the risk of breast cancer recurrence [38,39]. This observation may be linked to the inhibition of CSCs.…”

Section: Discussionmentioning

confidence: 99%

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

et al. 2012

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There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27 kip1 in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer. STEM

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“…Moreover, breast cancer patients who use statins or specifically, lipophilic statins showed improved recurrence-free survival. Statin users also had improved overall survival and cancer-specific survival (Ahern et al 2011;Manthravadi et al 2016). Mansourian et al (2016) in their meta-analysis suggested that statin use results in 21% reduction in breast cancer recurrence and 16% reduction in mortality rate.…”

Section: Effect Of Statins In Animal and Human Studiesmentioning

confidence: 99%

The role of statins as therapeutic agents in cancer

Sopková

Vidomanová²,

Strnádel³

et al. 2017

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Abstract.Statins are the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This enzyme catalyzes conversion of HMG-CoA to mevalonate, which are the intermediates in cholesterol biosynthetic pathway. Statins also play an important role in carcinogenesis, because they are able to affect the cancer cell metabolism. Their effect has been observed in several cellular processes, such as angiogenesis, metastasis, apoptosis and cell proliferation. However, these effects are highly dependent on type of cancer and individual statins vary in their antitumor potential. This review summarizes the recent epidemiological evidence and preclinical studies that showed effects of all clinically used statins in vitro and in vivo. We also consider the results of different observational and retrospective studies focused on association among statins and cancer risk which are still under open discussion.

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Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

Abstract: Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.

Cited by 325 publications

References 49 publications

Targeting tumor cell metabolism with statins

Targeting tumor cell metabolism with statins

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

The role of statins as therapeutic agents in cancer

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