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      Statin drugs to reduce breast cancer recurrence and mortality

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          Abstract

          Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.

          The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented.

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          The online version of this article (10.1186/s13058-018-1066-z) contains supplementary material, which is available to authorized users.

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          Most cited references106

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          2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

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            Chronic Inflammation and Cytokines in the Tumor Microenvironment

            Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF- α , IL-6, TGF- β , and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.
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              Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

              Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.
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                Author and article information

                Contributors
                chb106@pitt.edu
                brufskyam@upmc.edu
                oltvai@pitt.edu
                1-412-647-7813 , wellsa@upmc.edu
                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central (London )
                1465-5411
                1465-542X
                20 November 2018
                20 November 2018
                2018
                : 20
                : 144
                Affiliations
                [1 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Pathology, , University of Pittsburgh, ; Pittsburgh, 15231 PA USA
                [2 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Bioengineering, , University of Pittsburgh, ; Pittsburgh, 15231 PA USA
                [3 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Computational and Systems Biology, , University of Pittsburgh, ; Pittsburgh, 15231 PA USA
                [4 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, University of Pittsburgh Cancer Institute, , University of Pittsburgh, ; Pittsburgh, PA 15231 USA
                [5 ]Pittsburgh VA Health System, Pittsburgh, 15240 PA USA
                [6 ]ISNI 0000 0004 0455 1723, GRID grid.411487.f, Magee-Women’s Hospital of Pittsburgh, ; 300 Halket St., Pittsburgh, 15213 PA USA
                Author information
                http://orcid.org/0000-0002-1637-8150
                Article
                1066
                10.1186/s13058-018-1066-z
                6247616
                30458856
                b8209238-5e81-4015-b519-8ccf3bbf7b94
                © The Author(s). 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000738, U.S. Department of Veterans Affairs;
                Award ID: BX003368
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
                Award ID: TR000496
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CA199947
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                breast cancer,statins,metastasis,lipophilicity,prenylation,secondary prevention

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