Skip to main content

Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Do statins increase and Mediterranean diet decrease the risk of breast cancer?

BMC Medicine volume 12, Article number: 94 (2014) Cite this article

Abstract

Background

Physical exercise and healthy dietary habits are recommended to prevent breast cancer.

Discussion

Increased intake of omega-3 fatty acids associated with decreased omega-6 - resulting in higher omega-3 to omega-6 ratio compared with Western-type diet - is inversely associated with breast cancer risk. The modernized Mediterranean diet with high omega-3 to omega-6 ratio, high fiber and polyphenol intake, and consumption of low-glycemic index foods reduces overall cancer risk and specifically breast cancer risk. It has been suggested that consuming no more than one alcoholic drink per day, preferably wine, is preferable. Eliminating environmental contaminants, including endocrine disruptors, and favoring organic foods to increase polyphenol intake and the omega-3 to omega-6 ratios were also shown to be beneficial. Cholesterol-lowering statins may decrease antitumor defenses; are toxic for the mitochondria; decrease the omega-3 to omega-6 ratio; increase body mass index, insulin resistance and diabetic risk; and have been associated with an increased breast cancer risk.

Summary

Therefore, as well as making lifestyle changes to decrease breast cancer risk, we argue that physicians should carefully consider (and often avoid) therapies that may increase breast cancer or diabetes risk in high-risk women and women who wish to decrease their breast cancer risk.

Peer Review reports

Background

Breast cancer (BC) remains a leading cause of death from cancer and a scientific challenge for the medical community [1]. One critical issue is how to implement an effective preventive strategy [2]. Risk factors such as genetic predisposition cannot be modified whereas other factors (unhealthy diet, sedentary lifestyle) can be avoided [3]. Other strategies - for instance, decreasing the length of time a woman’s breast tissue is exposed to estrogens - may help prevent BC but have proved difficult to implement [4].

Increasing protective factors is critical, in particular among high-risk women [3]. The effects of dietary factors have been examined. For instance, dietary fats have been extensively studied in the prevention of BC [5–7] but only marine omega-3 fatty acids (n-3) may be protective [5]. In a meta-analysis of 21 independent prospective cohort studies, a significant reduction of BC risk with marine n-3 was found [8]. By contrast, omega-6 fatty acids (n-6) may increase BC risk [9, 10]. Although not all studies [9] show a link between n-6 and increased BC risk, the most recent and well-conducted studies actually indicate a positive association between n-6 and BC risk [10]. The pro-cancer effect of n-6 has also been suggested in randomized controlled trials in which n-6 intakes were modified [11, 12]. These trials were not specifically referring to BC but to cancers in general, in particular because the numbers of cancers were too small to analyze specific cancers. However, in the same way as smoking increases the risk of lung, bladder and BC, the data suggest that n-6 may increase the risk of several cancers. If n-6 increase cancer risk in general, it is reasonable to think that they may also increase BC risk as epidemiological studies did suggest [10].

As both n-3 and n-6 may contribute to BC risk individually (but in opposite directions), they may introduce confusion in their respective analyses. Thus, when analyzing the associations between n-3 and BC risk, it is critical that n-6 is included in the analyses. This is what Yang et al. did in their recent study [13]. They used the ratio of n-3 to n-6 in a meta-analysis including 274,135 women from 11 independent prospective studies and found that women with a higher n-3/n-6 ratio had a significantly lower risk of BC compared to women with low n-3/n-6 ratio [13].

Thus, all the factors influencing the n-3/n-6 ratio are critical in BC risk [14]. Increased intake of n-3 and decreased intake of n-6 through consumption of foods rich in n-3 and poor in n-6 [10, 15] - resulting in higher n-3/n-6 ratio - is therefore important to decrease BC risk [13, 14]. Polyphenol flavonoids that increase marine n-3 by about 30% - possibly through the stimulation of endogenous synthesis - without altering n-6 levels [16–18] also result in a significant increase in the n-3/n-6 ratio. In fact, flavonoids are associated with a decreased BC risk [19, 20].

Organic plant foods contain more polyphenols than similar conventional foods [21–24] and organic animal fat - for instance milk and milk products [25–27] - does have a higher n-3/n-6 ratio compared with conventional products. Thus, women who wish to decrease their BC risk may select organic plant and animal foods. Regarding food contaminants, a report from the American Institute of Medicine states that none of the potentially carcinogenetic contaminants, including organochlorine pesticides and polychlorinated biphenyls (PCBs), is linked to BC risk [28]. However, recent studies showing strong association between either estrogenic PCB congeners or dioxin and BC risk [29–31] do not confirm these optimistic conclusions. While further studies are needed, including studies of polymorphisms in the cytochrome P450 1A1 (CYP1A1) gene [32] (likely a confounding factor when studying the associations between PCBs and BC risk), these data are not reassuring. Regarding CYP1A1, this member of the CYP1 family participates in the metabolism of a vast number of xenobiotics including PCBs and dioxin. Four single nucleotide polymorphisms in CYP1A1 have been studied concerning their potential implication on BC. A recent meta-analysis pointed to the A2455G G allele as a risk factor for BC among subjects of Caucasian origin [32]. Thus, further studies analyzing the relationships between estrogenic PCB congeners and BC risk should include CYP1A1 polymorphisms as a potential marker of genetic predisposition to BC. In this context it is critical to recall that endocrine disruptors - such as phthalates - increase insulin resistance, diabetes and obesity [33–35], all of which increase BC risk (see below).

In the next section, we examine the critical importance of two major factors in breast cancer risk. One is protective (the modernized Mediterranean diet) whereas statins increase risk. The effects of both can be more easily understood at the light of the factors analyzed in the “Background” section.

Discussion

Statins and breast cancer risk

Other substances that influence both n-3/n-6 ratio and BC risk are the cholesterol-lowering statins. The effect of statins on cancer risk is a long story and still today there is no consensus [36–38]. The controversy began in 1996 with the publication of the Cholesterol and Recurrent Events (CARE) trial [39]. It was a double-blind randomized trial comparing the effects (versus placebo) of the cholesterol-lowering pravastatin against coronary event after myocardial infarction in 3,583 men and 576 women. Twelve out of 286 women in the statin group but only one out of 290 in the placebo group had BC at follow-up [39]. After that, most statin investigators took care not to include high-risk women in their trials [37] and carefully monitored them through repeated interim analyses for early detection of inter-group difference trends in cancer incidence. To further confuse the data, many statin trials were prematurely terminated - and it is likely that not all have been published - without valid scientific justification. Clearly, cancers diagnosed during drug trials are unlikely to be ex nihilo cancers and more likely to be dormant cancers clinically exposed by the treatment being investigated. As the process requires a minimal length of exposure, premature termination is the best way of avoiding the cancer issue in relation to any investigated drug. However, this process leads to confusion and prevents clarification of whether the investigated drug may increase cancer risk in the non-selected general population in whom the drug is then prescribed without precaution by unaware physicians. Despite this, a meta-analysis of clinical trials published in 2006 found a 33% increase in BC incidence with statins compared with a placebo [40]. It is noteworthy that confidence intervals were large (from 0.79 to 2.26) in that meta-analysis. However, there was great heterogeneity between trials (drug dosage, length of exposure) and curiously only five of the 26 randomized trials reported BC data [40], suggesting a striking lack of completeness of reporting of patient-relevant clinical trial outcomes, a well-known major source of bias and a substantial threat to the validity of clinical research findings [41]. In view of the inherent limitations of randomized trials discussed above, in particular premature termination and short follow-up, data from observational studies are critical to examine the statin-BC relationship.

In general, meta-analyses of observational studies reported no association between statin use and BC incidence. However, since high cholesterol may reduce cancer risk (see below), and as patients taking statins have spent most of their lives with high cholesterol - which is thought to lower cancer risk [37] - observational epidemiology is also facing difficulty in identifying statin cancer signals. In that context, even a lack of difference in BC risk between statin users and non-users in observational studies with long follow-up may suggest that statins increase BC risk. The recent demonstration that long-term (10-year) statin use was associated with a two-fold increase in BC risk among contemporary postmenopausal women [42] confirms the previous data suggesting that statins increase BC risk [36–40]. Regarding statin prescription and BC recurrence specifically, a Danish study suggested that one particular highly lipophilic statin (simvastatin) may be associated with a reduced risk [43]. However, as admitted by the authors, their study suffers major limitations. Briefly, the duration of exposure was short (a median of four years), the number of recurrences was small (n = 249 among statin users) and, very important, statin users and non-users were very different at baseline. This rendered adjustments for the many confounders - knowing that factors implicated in recurrence are not necessarily similar as those implicated in incidence - and between-group comparison very problematic. Still more important and admitted by the authors [43], confounding by indication likely explains their data [44] as the major indication for statin therapy is hypercholesterolemia, which is inherently associated with lower risk of BC recurrence [45].

The next question is whether there are biological explanations for the effect of statins on BC risk. First, statins interfere negatively with the metabolism of n-3 and n-6 - that is, they decrease the n-3/n-6 ratio [46–48] - which may in turn increase BC risk [13, 14]. Second, statins lower cholesterol, and low cholesterol is often (but not always) associated with a high cancer rate [37]. Inconsistency in the cholesterol-cancer data is likely to reflect the existence of confounding factors. One of these factors could be insulin resistance or metabolic syndrome [49, 50]. The Metabolic Syndrome and Cancer Project (Me-Can) - with more than 577,000 participants and a mean follow-up of 11.7 years - reported that cholesterol is negatively associated with BC risk, and this is a critical finding [50]. Third, a substance arising from cholesterol (dendrogenin A) is a key factor in the development of human BC [51], reinforcing the theory that high cholesterol may be protective. Fourth, statins are toxic to mitochondria [52, 53], and mitochondrial dysfunction contributes to tumorigenesis and cancer progression [54, 55]. Fifth, converging evidence supports the hypothesis that statins increase insulin resistance and new-onset diabetes, possibly (but not only) through mitochondrial toxicity in the muscles and other tissues [56–59]. This major side effect of statins was initially underestimated with regrettable consequences, some experts even stating that ‘the cardiovascular benefits of statin therapy exceed the diabetes hazard’ [60] while the trials upon which these claims were based were obviously flawed [61, 62]. By contrast, studies indicate highly significant increases of incident diabetes among statin users [63, 64], culminating in a 70% increase among postmenopausal women in the Women’s Health Initiative [65]. At the same time, it was learned that diabetes increases BC risk [66, 67] as well as the overall risk of cancers and cancer death [68]. As diabetes is also a marker of long-standing insulin resistance - with chronically high insulin levels and high fasting blood glucose - it is critical that metabolic syndromes have also been associated with BC risk [69–72].

Recently, investigators curiously claimed that hypercholesterolemia is a risk factor for BC and that lowering circulating cholesterol levels (or interfering with its conversion to 27-hydroxycholesterol) may be a useful strategy to prevent and/or treat BC [73]. However, the effects of 27-hydroxycholesterol were tested in rather artificial cellular and animal models of BC and hypercholesterolemia [73]. Studies using more humanized models are required before these data could have any clinical impact. Finally, statins have been shown to increase the number of immune regulatory T cells, which in turn may hinder antitumor defenses and increase cancer risk [74].

Thus, statins may increase BC risk through increased insulin resistance and new-onset diabetes, decreased n-3/n-6 ratio, cholesterol lowering, mitochondrial toxicity and an immunomodulatory effect. Statin use also results in skeletal muscle toxicity and decreased physical activity [56–58]. For decreasing BC risk, reducing insulin resistance, metabolic syndromes and diabetes risk is beneficial, as shown with the Mediterranean diet in the next section. Additionally, international guidelines [1–3] recommend that women aim for optimal physical activity, which is known to decrease risk for both diabetes [75, 76] and BC [1–4]. They also recommend that women should limit weight gain, especially around menopause, to reduce BC risk [1–3]. In that context, a recent report - 27,886 adults, 10-year follow-up - of a rapid increase in body mass index (equivalent to a 3- to 5-kg weight gain) among statin users compared with non-users is of concern [77]. Whatever the causes of that weight gain, be it reduced physical activity in relation with skeletal muscle toxicity [56–58], increased insulin resistance or increased caloric intake [77], it may contribute to the statin-induced increase in BC risk.

Regarding diabetes risk, increased fiber intake and consumption of flavonoids and n-3 are all inversely associated with diabetes risk [78–82]. In line with the fact that diabetes increases BC risk, not surprisingly fiber intake [83–86], flavonoids [19, 20] and n-3 [8, 10, 13, 14] are inversely associated with BC risk.

Finally, consumption of foods with a low glycemic impact - that is, foods with a low glycemic index (GI) - is associated with lower risks of diabetes [87, 88] and BC [89–92].

Modernized Mediterranean diet and breast cancer risk

The Mediterranean diet, the traditional dietary habits of people living around the Mediterranean Sea, is a well-known healthy dietary pattern [93]. A modernized version that includes traditional Mediterranean foods (for example, olive oil, non-refined wheat bread and wine) and foods not traditionally available to Mediterranean populations (for example, canola oil, margarines, low-fat dairy products) was tested in randomized trials and resulted in health benefits [93, 94]. The combination of high fiber, high n-3/n-6 ratio, high polyphenols and low-GI foods represents a healthy dietary pattern. Adoption of such a healthy diet is clearly associated with a lower BC risk [95–99]. Among women with early-stage BC, increased adherence to a similar healthy dietary pattern was associated with decreasing risk of overall death and death from non-BC causes (p = 0.003) [100]. There was also a trend toward less BC death, the lack of statistical significance being explained by the quite small (n = 1,900) sample size and small number of BC deaths (n = 128) [100]. More specifically, increased adherence to the Mediterranean diet pattern is also clearly associated with fewer cancers [101], specifically pancreatic [102], gastric [103], colorectal [104], hepatocellular [105], prostate [106] and breast [107–109]. This is not unexpected since the Mediterranean diet increases the n-3/n-6 ratio on the one hand [10, 93] and on the other decreases the risk of metabolic syndrome [110, 111] and diabetes [112, 113], both of which increase the risk of cancer - including BC - and cancer deaths [66–72]. Also, phenolic components of olive oil lowered body iron stores, which in turn may lower insulin resistance and metabolic syndrome [114]. Finally, the Mediterranean diet is an effective strategy for obtaining statistically and clinically significant weight loss [115–117], which in turn is considered a valuable strategy to reduce BC risk and improve survival after diagnosis [1–4].

The only limitation regarding the prevention of BC through adherence to the Mediterranean diet regards alcohol consumption. Moderate wine drinking is indeed a component of the traditional Mediterranean diet [93]. However, alcohol consumption increases BC risk [118], while the specific effect of wine is still unclear. The usual estimate for postmenopausal women who consume no more than one alcoholic drink per day is a 7% to 10% risk increase in comparison with non-drinkers [1, 2]. This is small but significant. Alcohol consumption may also increase BC recurrence [119]. Women who use postmenopausal hormones should take particular care with BC risk in relation to alcohol consumption [1–4]. In some [120, 121] but not all [122] studies, the excess BC risk with alcohol consumption is reduced by increasing the intake of folate. Accordingly, experts have stated that the Mediterranean way of drinking alcohol - regular and moderate consumption of polyphenol-rich wine mainly with folate-rich foods - does not appreciably influence the overall risk of cancer [123]. Given that moderate alcohol consumption also reduces the risk of cardiovascular disease [124], it appears that consuming approximately one alcoholic drink per day on average, including after BC diagnosis, is associated with optimal life expectancy without compromising BC-specific survival [125–127].

Summary

Adhering to a healthy dietary pattern, specifically the modernized Mediterranean diet [93, 94], should be the cornerstone of a lifestyle strategy to reduce BC risk in high-risk women and in women who wish to decrease their BC risk.

In the context of the Mediterranean diet, it is critical to increase plant and marine n-3 and decrease plant and animal n-6. High flavonoid consumption - which increases marine n-3 [16–18] - should be encouraged as it is associated with lower BC risk. To reduce insulin resistance and diabetes, which are associated with an increased BC risk, we argue that women should increase their consumption of fiber and favor low-GI foods. As far as possible, we feel that women should choose organic foods because of their effect on the n-3/n-6 ratio and because they contain fewer contaminants - and lower levels of each contaminant - in particular endocrine disruptor. Finally, we strongly argue that any drug thought to increase diabetes and/or BC risk - in particular, the statins and certain antihypertensive medications [128, 129] - should be considered with a great deal of precaution and even prohibited in high-risk women. To lower blood pressure or to decrease the risk of cardiovascular disease, physicians do have alternative drugs and lifestyle strategies and it would be tragically unwise to persist in prescribing these specific anticholesterol and antihypertensive drugs in women wishing to decrease their BC risk.

National and international guidelines recommend healthy diet and physical activity to decrease BC risk [130]. We agree with this advice. It is time, however, to go further and be more specific. A specific dietary pattern such as the modernized Mediterranean diet, and not simply ‘consuming a diet rich in vegetables and fruits’, should be adopted to decrease BC risk. This is also an effective way of maintaining a healthy weight and preventing diabetes and cardiovascular disease. This also applies to BC survivors to prevent recurrence and improve survival [131, 132].

Abbreviations

BC:

breast cancer

GI:

glycemic index

n-3:

omega-3 fatty acids

n-6:

omega-6 fatty acids

PCB:

polychlorinated biphenyls.

References

  1. 1.

    Matsen CB, Neumayer LA: Breast cancer: a review for the general surgeon. JAMA Surg. 2013, 148: 971-979. 10.1001/jamasurg.2013.3393.

  2. 2.

    Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, Blaydes JP, Brennan K, Brown NJ, Bryant HE, Bundred NJ, Burchell JM, Campbell AM, Carroll JS, Clarke RB, Coles CE, Cook GJ, Cox A, Curtin NJ, Dekker LV, Silva Idos S, Duffy SW, Easton DF, Eccles DM, Edwards DR, Edwards J, Evans D, Fenlon DF, Flanagan JM, Foster C, et al: Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Res. 2013, 15: R92-10.1186/bcr3493.

  3. 3.

    Breast Cancer Risk Assessment Tool. [http://www.cancer.gov/bcrisktool/]

  4. 4.

    Breast Cancer Prevention (PDQ®) - National Cancer Institute. [http://www.cancer.gov/cancertopics/pdq/prevention/breast/patient]

  5. 5.

    Khaw KT: Dietary fats and breast cancer risk. BMJ. 2013, 347: f4518-10.1136/bmj.f4518.

  6. 6.

    Alexander DD, Morimoto LM, Mink PJ, Lowe KA: Summary and meta-analysis of prospective studies of animal fat intake and breast cancer. Nutr Res Rev. 2010, 23: 169-179. 10.1017/S095442241000003X.

  7. 7.

    Prentice RL, Caan B, Chlebowski RT, Patterson R, Kuller LH, Ockene JK, Margolis KL, Limacher MC, Manson JE, Parker LM, Paskett E, Phillips L, Robbins J, Rossouw JE, Sarto GE, Shikany JM, Stefanick ML, Thomson CA, van Horn L, Vitolins MZ, Wactawski-Wende J, Wallace RB, Wassertheil-Smoller S, Whitlock E, Yano K, Adams-Campbell L, Anderson GL, Assaf AR, Beresford SA, Black HR, et al: Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006, 295: 629-642. 10.1001/jama.295.6.629.

  8. 8.

    Zheng JS, Hu XJ, Zhao YM, Yang J, Li D: Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ. 2013, 346: f3706-10.1136/bmj.f3706.

  9. 9.

    Zock PL, Katan MB: Linoleic acid intake and cancer risk: a review and meta-analysis. Am J Clin Nutr. 1998, 68: 142-153.

  10. 10.

    de Lorgeril M, Salen P: New insights into the health effects of dietary saturated and omega-6 and omega-3 polyunsaturated fatty acids. BMC Med. 2012, 10: 50-10.1186/1741-7015-10-50.

  11. 11.

    Pearce ML, Dayton S: Incidence of cancer in men on a diet high in polyunsaturated fat. Lancet. 1971, 1: 464-467.

  12. 12.

    de Lorgeril M, Salen P, Martin JL, Monjaud I, Boucher P, Mamelle N: Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate. Arch Intern Med. 1998, 158: 1181-1187. 10.1001/archinte.158.11.1181.

  13. 13.

    Yang B, Ren XL, Fu YQ, Gao JL, Duo L: Ratio of n-3/n-6 PUFAs and risk of breast cancer: a meta-analysis of 274,135 adult females from 11 independent prospective studies. BMC Cancer. 2014, 14: 105-10.1186/1471-2407-14-105.

  14. 14.

    de Lorgeril M, Salen P: Helping women to good health: breast cancer, omega-3/omega-6 lipids and related lifestyle factors. BMC Med. 2014, 12: 54-10.1186/1741-7015-12-54.

  15. 15.

    Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR: Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids. 2003, 38: 391-398. 10.1007/s11745-003-1074-0.

  16. 16.

    Toufektsian MC, Salen P, Laporte F, Tonelli C, de Lorgeril M: Dietary flavonoids increase plasma very long-chain (n-3) fatty acids in rats. J Nutr. 2011, 141: 37-41. 10.3945/jn.110.127225.

  17. 17.

    di Giuseppe R, de Lorgeril M, Salen P, Laporte F, Di Castelnuovo A, Krogh V, Siani A, Arnout J, Cappuccio FP, van Dongen M, Donati MB, de Gaetano G, Iacoviello L, European Collaborative Group of the IMMIDIET Project: Alcohol consumption and n-3 polyunsaturated fatty acids in healthy men and women from 3 European populations. Am J Clin Nutr. 2009, 89: 354-362.

  18. 18.

    de Lorgeril M, Salen P, Martin JL, Boucher F, de Leiris J: Interactions of wine drinking with omega-3 fatty acids in patients with coronary heart disease: a fish-like effect of moderate wine drinking. Am Heart J. 2008, 155: 175-181. 10.1016/j.ahj.2007.08.009.

  19. 19.

    Hui C, Qi X, Qianyong Z, Xiaoli P, Jundong Z, Mantian M: Flavonoids, flavonoid subclasses and breast cancer risk: a meta-analysis of epidemiologic studies. PLoS One. 2013, 8: e54318-10.1371/journal.pone.0054318.

  20. 20.

    Bosetti C, Spertini L, Parpinel M, Gnagnarella P, Lagiou P, Negri E, Franceschi S, Montella M, Peterson J, Dwyer J, Giacosa A, La Vecchia C: Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 2005, 14: 805-808. 10.1158/1055-9965.EPI-04-0838.

  21. 21.

    Dangour AD, Dodhia SK, Hayter A, Hayter A, Aikenhead A, Allen E, Lock K, Uauy R: Comparison of composition (nutrients and other substances) of organically and conventionally produced foodstuffs: a systematic review of the available literature. Report for the Food Standards Agency, July 2009, contract number: PAU221. [http://webarchive.nationalarchives.gov.uk/20120206100416/http://food.gov.uk/multimedia/pdfs/organicreviewappendices.pdf]

  22. 22.

    Benbrook C, Davis DR, Andrews PK: Methodologic flaws in selecting studies and comparing nutrient concentrations led Dangour et al. to miss the emerging forest amid the trees. Am J Clin Nutr. 2009, 90: 1700-1701. 10.3945/ajcn.2009.28605. author reply 1701

  23. 23.

    Benbrook C, Zhao X, Yanez J, Davies N, Andrews P: New evidence confirms the nutritional superiority of plant-based organic foods. An Organic Center State of Science Review, 2008. [http://www.organic-center.org/science.nutri.php?action=view&report_id=126]

  24. 24.

    Hallmann E, Lipowski J, Marszałek K, Rembiałkowska E: The seasonal variation in bioactive compounds content in juice from organic and non-organic tomatoes. Plant Foods Hum Nutr. 2013, 68: 171-176. 10.1007/s11130-013-0352-2.

  25. 25.

    Benbrook CM, Butler G, Latif MA, Leifert C, Davis DR: Organic production enhances milk nutritional quality by shifting fatty acid composition: a United States-wide, 18-month study. PLoS One. 2013, 8: e82429-10.1371/journal.pone.0082429.

  26. 26.

    Ellis KA, Innocent G, Grove-White D, Cripps P, McLean WG, Howard CV, Mihm M: Comparing the fatty acid composition of organic and conventional milk. J Dairy Sci. 2006, 89: 1938-1950. 10.3168/jds.S0022-0302(06)72261-5.

  27. 27.

    Tsiplakou E, Kotrotsios V, Hadjigeorgiou I, Zervas G: Differences in sheep and goats milk fatty acid profile between conventional and organic farming systems. J Dairy Res. 2010, 77: 343-349. 10.1017/S0022029910000270.

  28. 28.

    Smith-Bindman R: Environmental causes of breast cancer and radiation from medical imaging: findings from the Institute of Medicine report. Arch Intern Med. 2012, 172: 1023-1027.

  29. 29.

    Recio-Vega R, Velazco-Rodriguez V, Ocampo-Gómez G, Hernandez-Gonzalez S, Ruiz-Flores P, Lopez-Marquez F: Serum levels of polychlorinated biphenyls in Mexican women and breast cancer risk. J Appl Toxicol. 2011, 31: 270-278. 10.1002/jat.1672.

  30. 30.

    Cohn BA, Terry MB, Plumb M, Cirillo PM: Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50. Breast Cancer Res Treat. 2012, 136: 267-275. 10.1007/s10549-012-2257-4.

  31. 31.

    Warner M, Mocarelli P, Samuels S, Needham L, Brambilla P, Eskenazi B: Dioxin exposure and cancer risk in the Seveso Women’s Health Study. Environ Health Perspect. 2011, 119: 1700-1705. 10.1289/ehp.1103720.

  32. 32.

    Sergentanis TN, Economopoulos KP: Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010, 122: 459-469. 10.1007/s10549-009-0694-5.

  33. 33.

    Lind PM, Zethelius B, Lind L: Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care. 2012, 35: 1519-1524. 10.2337/dc11-2396.

  34. 34.

    Stahlhut RW, van Wijngaarden E, Dye TD, Cook S, Swan SH: Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 2007, 115: 876-882. 10.1289/ehp.9882.

  35. 35.

    Hatch EE, Nelson JW, Stahlhut RW, Webster TF: Association of endocrine disruptors and obesity: perspectives from epidemiological studies. Int J Androl. 2010, 33: 324-332. 10.1111/j.1365-2605.2009.01035.x.

  36. 36.

    Bonovas S, Filioussi K, Tsavaris N, Sitaras NM: Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol. 2005, 23: 8606-8612. 10.1200/JCO.2005.02.7045.

  37. 37.

    Ravnskov U, McCully KS, Rosch PJ: The statin-low cholesterol-cancer conundrum. QJM. 2012, 105: 383-388. 10.1093/qjmed/hcr243.

  38. 38.

    Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH: Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007, 50: 409-418. 10.1016/j.jacc.2007.02.073.

  39. 39.

    Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.

  40. 40.

    Dale KM, Coleman CI, Henyan NN, Kluger J, White CM: Statins and cancer risk: a meta-analysis. JAMA. 2006, 295: 74-80. 10.1001/jama.295.1.74.

  41. 41.

    Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, Hing C, Kwok CS, Pang C, Harvey I: Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess. 2010, 14: 1-193.

  42. 42.

    McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI: Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age. Cancer Epidemiol Biomarkers Prev. 2013, 22: 1529-1537. 10.1158/1055-9965.EPI-13-0414.

  43. 43.

    Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, Sørensen HT, Lash TL: Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011, 103: 1461-1468. 10.1093/jnci/djr291.

  44. 44.

    Bosco JL, Silliman RA, Thwin SS, Geiger AM, Buist DS, Prout MN, Yood MU, Haque R, Wei F, Lash TL: A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies. J Clin Epidemiol. 2010, 63: 64-74. 10.1016/j.jclinepi.2009.03.001.

  45. 45.

    Ozdemir BH, Akcali Z, Haberal M: Hypercholesterolemia impairs angiogenesis in patients with breast carcinoma and, therefore, lowers the risk of metastases. Am J Clin Pathol. 2004, 122: 696-703. 10.1309/HW2MYB5TVF4AM0Y4.

  46. 46.

    Jula A, Marniemi J, Rönnemaa T, Virtanen A, Huupponen R: Effects of diet and simvastatin on fatty acid composition in hypercholesterolemic men: a randomized controlled trial. Arterioscler Thromb Vasc Biol. 2005, 25: 1952-1959. 10.1161/01.ATV.0000177812.84927.fa.

  47. 47.

    de Lorgeril M, Salen P, Guiraud A, Zeghichi S, Boucher F, de Leiris J: Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease. Nutr Metab Cardiovasc Dis. 2005, 15: 36-41. 10.1016/j.numecd.2004.09.001.

  48. 48.

    Harris JI, Hibbeln JR, Mackey RH, Muldoon MF: Statin treatment alters serum n-3 and n-6 fatty acids in hypercholesterolemic patients. Prostaglandins Leukot Essent Fatty Acids. 2004, 71: 263-269. 10.1016/j.plefa.2004.06.001.

  49. 49.

    Osaki Y, Taniguchi S, Tahara A, Okamoto M, Kishimoto T: Metabolic syndrome and incidence of liver and breast cancers in Japan. Cancer Epidemiol. 2012, 36: 141-147. 10.1016/j.canep.2011.03.007.

  50. 50.

    Strohmaier S, Edlinger M, Manjer J, Stocks T, Bjørge T, Borena W, Häggström C, Engeland A, Nagel G, Almquist M, Selmer R, Tretli S, Concin H, Hallmans G, Jonsson H, Stattin P, Ulmer H: Total serum cholesterol and cancer incidence in the Metabolic syndrome and Cancer Project (Me-Can). PLoS One. 2013, 8: e54242-10.1371/journal.pone.0054242.

  51. 51.

    de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, Lacroix-Triki M, Filleron T, Pont F, Saati TA, Morisseau C, Hammock BD, Silvente-Poirot S, Poirot M: Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat Commun. 2013, 4: 1840.

  52. 52.

    Sirvent P, Fabre O, Bordenave S, Hillaire-Buys D, Raynaud De Mauverger E, Lacampagne A, Mercier J: Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins. Toxicol Appl Pharmacol. 2012, 259: 263-268. 10.1016/j.taap.2012.01.008.

  53. 53.

    Kaufmann P, Török M, Zahno A, Waldhauser KM, Brecht K, Krähenbühl S: Toxicity of statins on rat skeletal muscle mitochondria. Cell Mol Life Sci. 2006, 63: 2415-2425. 10.1007/s00018-006-6235-z.

  54. 54.

    Wallace DC: Mitochondria and cancer. Nat Rev Cancer. 2012, 12: 685-698. 10.1038/nrc3365.

  55. 55.

    Cuezva JM, Krajewska M, de Heredia ML, Krajewski S, Santamaría G, Kim H, Zapata JM, Marusawa H, Chamorro M, Reed JC: The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res. 2002, 62: 6674-6681.

  56. 56.

    Golomb BA, Evans MA, Dimsdale JE, White HL: Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med. 2012, 172: 1180-1182.

  57. 57.

    Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F: Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013, 61: 44-53. 10.1016/j.jacc.2012.09.036.

  58. 58.

    Bouitbir J, Charles AL, Rasseneur L, Dufour S, Piquard F, Geny B, Zoll J: Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. J Appl Physiol. 2011, 111: 1477-1483. 10.1152/japplphysiol.00107.2011.

  59. 59.

    Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK: Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol. 2010, 55: 1209-1216. 10.1016/j.jacc.2009.10.053.

  60. 60.

    Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ: Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012, 380: 565-571. 10.1016/S0140-6736(12)61190-8.

  61. 61.

    de Lorgeril M, Salen P, Abramson J, Dodin S, Hamazaki T, Kostucki W, Okuyama H, Pavy B, Rabaeus M: Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med. 2010, 170: 1032-1036. 10.1001/archinternmed.2010.184.

  62. 62.

    de Lorgeril M, Salen P, Defaye P, Rabaeus M: Recent findings on the health effects of omega-3 fatty acids and statins, and their interactions: do statins inhibit omega-3?. BMC Med. 2013, 11: 5-10.1186/1741-7015-11-5.

  63. 63.

    Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM: Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013, 346: f2610-10.1136/bmj.f2610.

  64. 64.

    Zaharan NL, Williams D, Bennett K: Statins and risk of treated incident diabetes in a primary care population. Br J Clin Pharmacol. 2013, 75: 1118-1124. 10.1111/j.1365-2125.2012.04403.x.

  65. 65.

    Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y: Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012, 172: 144-152. 10.1001/archinternmed.2011.625.

  66. 66.

    Boyle P, Boniol M, Koechlin A, Robertson C, Valentini F, Coppens K, Fairley LL, Boniol M, Zheng T, Zhang Y, Pasterk M, Smans M, Curado MP, Mullie P, Gandini S, Bota M, Bolli GB, Rosenstock J, Autier P: Diabetes and breast cancer risk: a meta-analysis. Br J Cancer. 2012, 107: 1608-1617. 10.1038/bjc.2012.414.

  67. 67.

    Redaniel MT, Jeffreys M, May MT, Ben-Shlomo Y, Martin RM: Associations of type 2 diabetes and diabetes treatment with breast cancer risk and mortality: a population-based cohort study among British women. Cancer Causes Control. 2012, 23: 1785-1795. 10.1007/s10552-012-0057-0.

  68. 68.

    Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J, Emerging Risk Factors Collaboration: Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011, 364: 829-841.

  69. 69.

    Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD: Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009, 101: 48-60. 10.1093/jnci/djn415.

  70. 70.

    Rosato V, Bosetti C, Talamini R, Levi F, Montella M, Giacosa A, Negri E, La Vecchia C: Metabolic syndrome and the risk of breast cancer in postmenopausal women. Ann Oncol. 2011, 22: 2687-2692. 10.1093/annonc/mdr025.

  71. 71.

    Minicozzi P, Berrino F, Sebastiani F, Falcini F, Vattiato R, Cioccoloni F, Calagreti G, Fusco M, Vitale MF, Tumino R, Sigona A, Budroni M, Cesaraccio R, Candela G, Scuderi T, Zarcone M, Campisi I, Sant M: High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease. Eur J Cancer. 2013, 49: 3881-3888. 10.1016/j.ejca.2013.08.004.

  72. 72.

    Agnoli C, Berrino F, Abagnato CA, Muti P, Panico S, Crosignani P, Krogh V: Metabolic syndrome and postmenopausal breast cancer in the ORDET cohort: a nested case–control study. Nutr Metab Cardiovasc Dis. 2010, 20: 41-48. 10.1016/j.numecd.2009.02.006.

  73. 73.

    Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP: 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013, 342: 1094-1098. 10.1126/science.1241908.

  74. 74.

    Goldstein MR, Mascitelli L, Pezzetta F: The double-edged sword of statin immunomodulation. Int J Cardiol. 2009, 135: 128-130. 10.1016/j.ijcard.2008.01.023.

  75. 75.

    Dengel DR, Hagberg JM, Pratley RE, Rogus EM, Goldberg AP: Improvements in blood pressure, glucose metabolism, and lipoprotein lipids after aerobic exercise plus weight loss in obese, hypertensive middle-aged men. Metabolism. 1998, 47: 1075-1082. 10.1016/S0026-0495(98)90281-5.

  76. 76.

    Smutok MA, Reece C, Kokkinos PF: Aerobic versus strength training for risk factor intervention in middle-aged men at high risk for coronary heart disease. Metabolism. 1993, 42: 177-184. 10.1016/0026-0495(93)90032-J.

  77. 77.

    Sugiyama T, Tsugawa Y, Tseng CH, Kobayashi Y, Shapiro MF: Different time trends of caloric and fat intake between statin users and nonusers among US adults: gluttony in the time of statins?. JAMA Intern Med. 2014, [Epub ahead of print]

  78. 78.

    Yao B, Fang H, Xu W, Yan Y, Xu H, Liu Y, Mo M, Zhang H, Zhao Y: Dietary fiber intake and risk of type 2 diabetes: a dose–response analysis of prospective studies. Eur J Epidemiol. 2014, 29: 79-88. 10.1007/s10654-013-9876-x.

  79. 79.

    Zamora-Ros R, Forouhi NG, Sharp SJ, González CA, Buijsse B, Guevara M, van der Schouw YT, Amiano P, Boeing H, Bredsdorff L, Fagherazzi G, Feskens EJ, Franks PW, Grioni S, Katzke V, Key TJ, Khaw KT, Kühn T, Masala G, Mattiello A, Molina-Montes E, Nilsson PM, Overvad K, Perquier F, Redondo ML, Ricceri F, Rolandsson O, Romieu I, Roswall N, Scalbert A, et al: Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations. J Nutr. 2014, 144: 335-343. 10.3945/jn.113.184945.

  80. 80.

    Zheng JS, Huang T, Yang J, Fu YQ, Li D: Marine N-3 polyunsaturated fatty acids are inversely associated with risk of type 2 diabetes in Asians: a systematic review and meta-analysis. PLoS One. 2012, 7: e44525-10.1371/journal.pone.0044525.

  81. 81.

    Djoussé L, Biggs ML, Lemaitre RN, King IB, Song X, Ix JH, Mukamal KJ, Siscovick DS, Mozaffarian D: Plasma omega-3 fatty acids and incident diabetes in older adults. Am J Clin Nutr. 2011, 94: 527-533.

  82. 82.

    Brostow DP, Odegaard AO, Koh WP, Duval S, Gross MD, Yuan JM, Pereira MA: Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. Am J Clin Nutr. 2011, 94: 520-526. 10.3945/ajcn.110.009357.

  83. 83.

    Suzuki R, Rylander-Rudqvist T, Ye W, Saji S, Adlercreutz H, Wolk A: Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status–a prospective cohort study among Swedish women. Int J Cancer. 2008, 122: 403-412. 10.1002/ijc.23060.

  84. 84.

    Zhang CX, Ho SC, Cheng SZ, Chen YM, Fu JH, Lin FY: Effect of dietary fiber intake on breast cancer risk according to estrogen and progesterone receptor status. Eur J Clin Nutr. 2011, 65: 929-936. 10.1038/ejcn.2011.57.

  85. 85.

    Ferrari P, Rinaldi S, Jenab M, Lukanova A, Olsen A, Tjønneland A, Overvad K, Clavel-Chapelon F, Fagherazzi G, Touillaud M, Kaaks R, von Rüsten A, Boeing H, Trichopoulou A, Lagiou P, Benetou V, Grioni S, Panico S, Masala G, Tumino R, Polidoro S, Bakker MF, van Gils CH, Ros MM, Bueno-de-Mesquita HB, Krum-Hansen S, Engeset D, Skeie G, Pilar A, Sánchez MJ, et al: Dietary fiber intake and risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study. Am J Clin Nutr. 2013, 97: 344-353. 10.3945/ajcn.112.034025.

  86. 86.

    Park Y, Brinton LA, Subar AF, Hollenbeck A, Schatzkin A: Dietary fiber intake and risk of breast cancer in postmenopausal women: the National Institutes of Health-AARP Diet and Health Study. Am J Clin Nutr. 2009, 90: 664-671. 10.3945/ajcn.2009.27758.

  87. 87.

    Oba S, Nanri A, Kurotani K, Goto A, Kato M, Mizoue T, Noda M, Inoue M, Tsugane S, Japan Public Health Center-based Prospective Study Group: Dietary glycemic index, glycemic load and incidence of type 2 diabetes in Japanese men and women: the Japan public health center-based prospective study. Nutr J. 2013, 2: 165.

  88. 88.

    Salmerón J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC: Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. JAMA. 1997, 277: 472-477. 10.1001/jama.1997.03540300040031.

  89. 89.

    Choi Y, Giovannucci E, Lee JE: Glycaemic index and glycaemic load in relation to risk of diabetes-related cancers: a meta-analysis. Br J Nutr. 2012, 108: 1934-1947. 10.1017/S0007114512003984.

  90. 90.

    Dong JY, Qin LQ: Dietary glycemic index, glycemic load, and risk of breast cancer: meta-analysis of prospective cohort studies. Breast Cancer Res Treat. 2011, 126: 287-294. 10.1007/s10549-011-1343-3.

  91. 91.

    Lajous M, Boutron-Ruault MC, Fabre A, Clavel-Chapelon F, Romieu I: Carbohydrate intake, glycemic index, glycemic load, and risk of postmenopausal breast cancer in a prospective study of French women. Am J Clin Nutr. 2008, 87: 1384-1391.

  92. 92.

    Sieri S, Pala V, Brighenti F, Pellegrini N, Muti P, Micheli A, Evangelista A, Grioni S, Contiero P, Berrino F, Krogh V: Dietary glycemic index, glycemic load, and the risk of breast cancer in an Italian prospective cohort study. Am J Clin Nutr. 2007, 86: 1160-1166.

  93. 93.

    de Lorgeril M: Mediterranean diet and cardiovascular disease: historical perspective and latest evidence. Curr Atheroscler Rep. 2013, 15: 370.

  94. 94.

    de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N: Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999, 99: 779-785. 10.1161/01.CIR.99.6.779.

  95. 95.

    Brennan SF, Cantwell MM, Cardwell CR, Velentzis LS, Woodside JV: Dietary patterns and breast cancer risk: a systematic review and meta-analysis. Am J Clin Nutr. 2010, 91: 1294-1302.

  96. 96.

    Männistö S, Dixon LB, Balder HF, Virtanen MJ, Krogh V, Khani BR, Berrino F, van den Brandt PA, Hartman AM, Pietinen P, Tan F, Wolk A, Goldbohm RA: Dietary patterns and breast cancer risk: results from three cohort studies in the DIETSCAN project. Cancer Causes Control. 2005, 16: 725-733. 10.1007/s10552-005-1763-7.

  97. 97.

    Cottet V, Touvier M, Fournier A, Touillaud MS, Lafay L, Clavel-Chapelon F, Boutron-Ruault MC: Postmenopausal breast cancer risk and dietary patterns in the E3N-EPIC prospective cohort study. Am J Epidemiol. 2009, 170: 1257-1267. 10.1093/aje/kwp257.

  98. 98.

    Link LB, Canchola AJ, Bernstein L, Clarke CA, Stram DO, Ursin G, Horn-Ross PL: Dietary patterns and breast cancer risk in the California Teachers Study cohort. Am J Clin Nutr. 2013, 98: 1524-1532.

  99. 99.

    Sieri S, Krogh V, Pala V, Muti P, Micheli A, Evangelista A, Tagliabue G, Berrino F: Dietary patterns and risk of breast cancer in the ORDET cohort. Cancer Epidemiol Biomarkers Prev. 2004, 13: 567-572.

  100. 100.

    Kwan ML, Weltzien E, Kushi LH, Castillo A, Slattery ML, Caan BJ: Dietary patterns and breast cancer recurrence and survival among women with early-stage breast cancer. J Clin Oncol. 2009, 27: 919-926. 10.1200/JCO.2008.19.4035.

  101. 101.

    Grosso G, Buscemi S, Galvano F, Mistretta A, Marventano S, La Vela V, Drago F, Gangi S, Basile F, Biondi A: Mediterranean diet and cancer: epidemiological evidence and mechanism of selected aspects. BMC Surg. 2013, 13: S14-10.1186/1471-2482-13-S2-S14.

  102. 102.

    Bosetti C, Turati F, Dal Pont A, Ferraroni M, Polesel J, Negri E, Serraino D, Talamini R, La Vecchia C, Zeegers MP: The role of Mediterranean diet on the risk of pancreatic cancer. Br J Cancer. 2013, 109: 1360-1366. 10.1038/bjc.2013.345.

  103. 103.

    Praud D, Bertuccio P, Bosetti C, Turati F, Ferraroni M, La Vecchia C: Adherence to the Mediterranean diet and gastric cancer risk in Italy. Int J Cancer. 2014, 134: 2935-2941. 10.1002/ijc.28620.

  104. 104.

    Bamia C, Lagiou P, Buckland G, Grioni S, Agnoli C, Taylor AJ, Dahm CC, Overvad K, Olsen A, Tjønneland A, Cottet V, Boutron-Ruault MC, Morois S, Grote V, Teucher B, Boeing H, Buijsse B, Trichopoulos D, Adarakis G, Tumino R, Naccarati A, Panico S, Palli D, Bueno-de-Mesquita HB, van Duijnhoven FJ, Peeters PH, Engeset D, Skeie G, Lund E, Sánchez MJ, et al: Mediterranean diet and colorectal cancer risk: results from a European cohort. Eur J Epidemiol. 2013, 28: 317-328. 10.1007/s10654-013-9795-x.

  105. 105.

    Turati F, Trichopoulos D, Polesel J, Bravi F, Rossi M, Talamini R, Franceschi S, Montella M, Trichopoulou A, La Vecchia C, Lagiou P: Mediterranean diet and hepatocellular carcinoma. J Hepatol. 2014, 60: 606-611. 10.1016/j.jhep.2013.10.034.

  106. 106.

    Kenfield SA, Dupre N, Richman EL, Stampfer MJ, Chan JM, Giovannucci EL: Mediterranean diet and prostate cancer risk and mortality in the health professionals follow-up study. Eur Urol. 2014, 65: 887-894. 10.1016/j.eururo.2013.08.009.

  107. 107.

    Buckland G, Travier N, Cottet V, González CA, Luján-Barroso L, Agudo A, Trichopoulou A, Lagiou P, Trichopoulos D, Peeters PH, May A, Bueno-de-Mesquita HB, Bvan Duijnhoven FJ, Key TJ, Allen N, Khaw KT, Wareham N, Romieu I, McCormack V, Boutron-Ruault M, Clavel-Chapelon F, Panico S, Agnoli C, Palli D, Tumino R, Vineis P, Amiano P, Barricarte A, Rodríguez L, Sanchez MJ, et al: Adherence to the Mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study. Int J Cancer. 2013, 132: 2918-2927. 10.1002/ijc.27958.

  108. 108.

    Demetriou CA, Hadjisavvas A, Loizidou MA, Loucaides G, Neophytou I, Sieri S, Kakouri E, Middleton N, Vineis P, Kyriacou K: The Mediterranean dietary pattern and breast cancer risk in Greek-Cypriot women: a case–control study. BMC Cancer. 2012, 12: 113-10.1186/1471-2407-12-113.

  109. 109.

    Trichopoulou A, Bamia C, Lagiou P, Trichopoulos D: Conformity to traditional Mediterranean diet and breast cancer risk in the Greek EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Am J Clin Nutr. 2010, 92: 620-625.

  110. 110.

    Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB: The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol. 2011, 57: 1299-1313. 10.1016/j.jacc.2010.09.073.

  111. 111.

    Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M, D’Andrea F, Giugliano D: Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004, 292: 1440-1446. 10.1001/jama.292.12.1440.

  112. 112.

    Martínez-González MA, de la Fuente-Arrillaga C, Nunez-Cordoba JM, Basterra-Gortari FJ, Beunza JJ, Vazquez Z, Benito S, Tortosa A, Bes-Rastrollo M: Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ. 2008, 336: 1348-1351. 10.1136/bmj.39561.501007.BE.

  113. 113.

    Salas-Salvadó J, Bullo M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Romaguera D, Lapetra J, Lamuela-Raventós RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez-González MA: Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med. 2014, 160: 1-10. 10.7326/G14-3001.

  114. 114.

    Mascitelli L, Goldstein MR: Mediterranean diet, lower body iron stores and metabolic syndrome. Int J Clin Pract. 2011, 65: 1110-10.1111/j.1742-1241.2011.02709.x.

  115. 115.

    Shai I, Schwarzfuchs D, Henkin Y, Witkow S, Greenberg I, Golan R, Fraser D, Bolotin A, Vardi H, Tangi-Rozental O, Zuk-Ramot R, Sarusi B, Brickner D, Schwartz Z, Sheiner E, Marko R, Katorza E, Thiery J, Fiedler GM, Blüher M, Stumvoll M, Stampfer MJ, Dietary Intervention Randomized Controlled Trial (DIRECT) Group: Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008, 359: 229-241. 10.1056/NEJMoa0708681.

  116. 116.

    Richard C, Royer MM, Couture P, Cianflone K, Rezvani R, Desroches S, Lamarche B: Effect of the Mediterranean diet on plasma adipokine concentrations in men with metabolic syndrome. Metabolism. 2013, 62: 1803-1810. 10.1016/j.metabol.2013.07.012.

  117. 117.

    Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, O’Dea K, Desmond PV, Johnson NA, Wilson AM: The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013, 59: 138-143. 10.1016/j.jhep.2013.02.012.

  118. 118.

    Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE: Alcohol consumption and breast cancer risk in the Women’s Health Study. Am J Epidemiol. 2007, 165: 667-676. 10.1093/aje/kwk054.

  119. 119.

    Kwan ML, Kushi LH, Weltzien E, Tam EK, Castillo A, Sweeney C, Caan BJ: Alcohol consumption and breast cancer recurrence and survival among women with early-stage breast cancer: the life after cancer epidemiology study. J Clin Oncol. 2010, 28: 4410-4416. 10.1200/JCO.2010.29.2730.

  120. 120.

    Tjønneland A, Christensen J, Olsen A, Stripp C, Nissen SB, Overvad K, Thomsen BL: Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr. 2006, 60: 280-286. 10.1038/sj.ejcn.1602313.

  121. 121.

    Baglietto L, English DR, Gertig DM, Hopper JL, Giles GG: Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. BMJ. 2005, 331: 807-10.1136/bmj.38551.446470.06.

  122. 122.

    Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG: Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr. 2006, 83: 895-904.

  123. 123.

    Giacosa A, Barale R, Bavaresco L, Gatenby P, Gerbi V, Janssens J, Johnston B, Kas K, La Vecchia C, Mainguet P, Morazzoni P, Negri E, Pelucchi C, Pezzotti M, Rondanelli M: Cancer prevention in Europe: the Mediterranean diet as a protective choice. Eur J Cancer Prev. 2013, 22: 90-95. 10.1097/CEJ.0b013e328354d2d7.

  124. 124.

    Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano G: Cardiovascular and overall mortality risk in relation to alcohol consumption in patients with cardiovascular disease. Circulation. 2010, 121: 1951-1959. 10.1161/CIRCULATIONAHA.109.865840.

  125. 125.

    Newcomb PA, Kampman E, Trentham-Dietz A, Egan KM, Titus LJ, Baron JA, Hampton JM, Passarelli MN, Willett WC: Alcohol consumption before and after breast cancer diagnosis: associations with survival from breast cancer, cardiovascular disease, and other causes. J Clin Oncol. 2013, 31: 1939-1946. 10.1200/JCO.2012.46.5765.

  126. 126.

    Demark-Wahnefried W, Goodwin PJ: To your health: how does the latest research on alcohol and breast cancer inform clinical practice?. J Clin Oncol. 2013, 31: 1917-1919. 10.1200/JCO.2013.49.0466.

  127. 127.

    Arranz S, Chiva-Blanch G, Valderas-Martínez P, Medina-Remón A, Lamuela-Raventós RM, Estruch R: Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer. Nutrients. 2012, 4: 759-781. 10.3390/nu4070759.

  128. 128.

    Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE: Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med. 2013, 173: 1629-1637. 10.1001/jamainternmed.2013.9071.

  129. 129.

    Bhaskaran K, Douglas I, Evans S, van Staa T, Smeeth L: Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ. 2012, 344: e2697-10.1136/bmj.e2697.

  130. 130.

    Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K, Gansler T, Society AC, Nutrition and Physical Activity Guidelines Advisory Committee: American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2010, 2012: 30-67.

  131. 131.

    Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, Bandera EV, Hamilton KK, Grant B, McCullough M, Byers T, Gansler T: Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012, 62: 243-274.

  132. 132.

    Wolin KY, Colditz GA: Cancer and beyond: healthy lifestyle choices for cancer survivors. J Natl Cancer Inst. 2013, 105: 593-594. 10.1093/jnci/djt052.

Download references

Acknowledgements

MdeL and PS receive research grants (through Grenoble University School of Medicine) from the European Community and from the Barilla G&R F.lli Company.

Author information

Affiliations

  1. Laboratoire TIMC-IMAG, CNRS UMR 5525, PRETA Cœur & Nutrition, and Faculté de Médecine, Université Joseph Fourier, Grenoble, France
    • Michel de Lorgeril
    •  & Patricia Salen
Authors
  1. Search for Michel de Lorgeril in:
  2. Search for Patricia Salen in:

Corresponding author

Correspondence to Michel de Lorgeril.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MdeL drafted the manuscript. PS critically revised the manuscript and gave final approval for publication. Both authors read and approved the final manuscript.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Lorgeril, M., Salen, P. Do statins increase and Mediterranean diet decrease the risk of breast cancer?. BMC Med 12, 94 (2014). https://doi.org/10.1186/1741-7015-12-94

Download citation

Keywords

  • Cholesterol
  • Diabetes
  • Endocrine disruptors
  • Insulin resistance
  • Organic foods
  • Polyphenols
  • Statins

BMC Medicine

ISSN: 1741-7015

Contact us