Frontiers journals are at the top of citation and impact metrics

Systematic Review ARTICLE

Front. Nutr., 14 May 2019 | https://doi.org/10.3389/fnut.2019.00062

Dairy Products: Is There an Impact on Promotion of Prostate Cancer? A Review of the Literature

  • 1Clinicas Viver, Lisbon, Portugal
  • 2European University of Lisbon, Lisbon, Portugal
  • 3Faculdade de Medicina, Instituto de Saúde Ambiental, Universidade de Lisboa, Lisbon, Portugal
  • 4Instituto de Ciências da Saúde, Universidade Católica Portuguesa, Lisbon, Portugal
  • 5University Hospital of Santa Maria, University of Lisbon, Lisbon, Portugal
  • 6Centre for Interdisciplinary Research in Health, Universidade Católica Portuguesa, Lisbon, Portugal

This review of the literature aims to study potential associations between high consumption of milk and/or dairy products and prostate cancer (PC). Literature is scarce, yet there is a direct relationship between mTORC1 activation and PC; several ingredients in milk/dairy products, when in high concentrations, increase signaling of the mTORC1 pathway. However, there are no studies showing an unequivocal relationship between milk products PC initiation and/or progression. Three different reviews were conducted with articles published in the last 5 years: (M1) PC and intake of dairy products, taking into account the possible mTORC1signaling mechanism; (M2) Intake of milk products and incidence/promotion of PC; (M3) mTORC1 activation signaling pathway, levels of IGF-1 and PC; (M4) mTORC pathway and dairy products. Of the 32 reviews identified, only 21 met the inclusion criteria and were analyzed. There is little scientific evidence that directly link the three factors: incidence/promotion of PC, intake of dairy products and PC, and PC and increased mTORC1 signaling. Persistent hyper-activation of mTORC1 is associated with PC promotion. The activity of exosomal mRNA in cellular communication may lead to different impacts of different types of milk and whether or not mammalian milks will have their own characteristics within each species. Based on this review of the literature, it is possible to establish a relationship between the consumption of milk products and the progression of PC; we also found a possible association with PC initiation, hence it is likely that the intake of dairy products should be reduced or minimized in mens' diet.

Introduction

Prostate cancer (PC) is the most common in both sexes combined and the second most common cancer in males. This type of cancer will be diagnosed in one in each seven males (1). According to GLOBOCAN (2), in 2012 and all over the world, 1,1 million men diagnosed with PC which resulted in 307,000 deaths. This number corresponds to 15% of total cancers diagnosed in males and about 70% are registered in most developed regions. The PC incidence varies in all the world; however, the higher rates occur in Australia/New Zealand and North America (ASR 111,6 e 97,2 per 100,000). The incidence rate in western countries is very high and it can reach 80 to 100 cases per 100,000 persons per year. In Africa (North and East) and Eastern Asia, the incidence is lower: 10 to 20 cases per 100,000 persons.

In Portugal, according to the Portuguese Association of Urology, PC constitutes the second cause of death by cancer, right behind lung cancer, but is also the most frequent cancer in males above 50 years old. It is estimated an incidence of 82 cases per 100,000 inhabitants and a mortality rate of 33 per 100,000. PC represents about 3.5% of death causes and more than 10% of death by cancer.

PC incidence is higher in developed countries: There is a positive relationship between SIR (Standard Incidence Rate) and Development Index and its components, such as human life expectancy at birth, years of compulsory education and gross per capita income (3, 4). Another reason to justify this high PC incidence in developed countries may be connected with diagnosis improvement and the introduction of the routine evaluation of the specific antigen of PC (PSA) and the prostate biopsy, besides the population aging and the increase risk factors (5).

Prostate Cancer and Milk/Diet

Western diet, rich in milk and dairy products, animal fat and sugars, with high calcium contents, is also connected to the risk growth of PC (68). Greater per capita milk consumption are probably correlated with higher PC incidence and mortality according World Cancer Research Foundation 2007 (913).

Milk consumption has always been associated to child mortality reduction, increased fertility, increase of children's BMI and of adolescence growth (1416). Milk, relevant sources of proteins and other macromolecules provides various nutrients and bioactive molecules to support their growth and development (15). However, milk consumption only in adolescence was associated to an increase of 3.2 times the risk of advanced PC in the cohort population of 8894 Icelandic men (13).

According to the conclusions of a 2016 meta-analysis pursued by investigators from the Republic of China, the ingestion of dairy products has no significant impact in the mortality risk increase in all kind of cancers while a small daily ingestion of dairy products can even reduce the risk based on a non-linear module (17). However, the same study concludes fat milk consumption by men may contribute significantly to the increase of PC mortality risk. There is thus a direct relationship between milk ingestion and increased PC mortality (17, 18).

According to some authors, the increase of 35 gr./per day of milk proteins consumption was associated to a 32% increase of PC risk (19). In some Cohort studies, results are less conclusive regarding milk negative impact (2022). According to Nacional Cancer Institute (USA), more than 2.6 million people in USA are PC survivors and they have potentially improved the prognosis by adopting healthy lifestyle habits (23). Limit the consumption of meat and dairy products, particularly high fat, is part of the recommendations to reduce the risk of PC progression (24).

Importance of Androgen Receptor for Prostate Cancer

Androgen receptor (AR) mediated signaling is required for the proliferation of prostate cancer cells and is a critical receptor for the development and progression of prostate (25). Prostate cancer is dependent on androgen receptor signaling (25). The high concentration of steroid hormones present in dairy products may, very probably, be related to the effect these products have on the initiation and promotion of prostate and breast cancer. (26). Dairy products concentrate hormones as insulin-like growth factor-1 (IGF-1). (2729). In recent years, according to epidemiological evidence, the risk of colon, pancreatic, endometrial, breast, and prostate tumors is associated with high IGF-1 levels (30) and increased IGF/IGF-1R signaling is implicated in all stages of carcinoma progression (31, 32). On the other hand, according to a recently published review article, the scientific evidence points to the intake of milk and dairy products that meets the recommended nutrients that protect against the most prevalent chronic diseases, however, the evidence for PC is inconsistent (33). The androgen receptors and the signaling mechanism of rapamycin complex 1 (mTORC1) and PI3 kinase-AKT may be key points in the PC. (34, 35) and its dysregulation is common in many human cancers such as prostate, colon, breast and thyroid (36). The objective of this review of the literature is to evaluate a potential correlation between milk and dairy consumption and the incidence and progression of prostate cancer, given that:

- The signaling pathway of mTORC1 and P13 Kinase-AKT is a cancer-promoting mechanism (33, 3742).

- Signaling of mTOR complex1 can be activated by BCAAs (leucine), Glutamine, Insulin, IGF-1, glucose, ATP (4347).

- Milk provides nutrients that can activate mTORC signaling pathways (48, 49).

Materials and Methods

Information Sources and Keywords

A search was performed in the PubMed (US National Library of Medicine) using the terms MeSH (Medical Subject Headings) identified and corresponding to the following keywords: prostate cancer, dairy products, milk, IGF, mTORC1.

The various searches were performed using only MeSH terms:

“Prostatic Neoplasms”[MeSH], “Dairy Products”[MeSH], “Cultured Milk Products”[MeSH], “mTOR protein, human” [Supplementary Concept], “Insulin-Like Growth Factor I”[MeSH], “mechanistic target of rapamycin complex 1” [Supplementary Concept], “TOR Serine-Threonine Kinases”[MeSH].

The research was done according to the following research criteria relating the factors as follows (Figure 1):

a- Relate the incidence of PC to the consumption of dairy products taking into account the possible signaling mechanism of mTORC1. Research M1- with “Prostatic Neoplasms” (MeSH) AND (“Dairy Products” [MeSH] OR “Cultured Milk Products” [MeSH]) AND (“MTOR protein, human” [Supplementary Concept] OR “Multiprotein Complexes”] OR “Insulin-Like Growth Factor I” [MeSH])

b- Relate the intake of dairy products with the incidence of PC-Research M2—with “Prostatic Neoplasms” (MeSH) AND (“Dairy Products”) OR “Cultured Milk Products” (MeSH).

c- Relate the possible mechanism of activation of the mTORC1 signaling pathway, IGF1 levels with the PC-Research M3 with (Insulin-Like Growth Factor I [MeSH] OR mtor protein [MeSH Terms] OR mechanistic target of rapamycin complex 1 [Supplementary Concept] OR “TOR Serine-Threonine Kinases” [MeSH]) AND (prostate cancer [MeSH Terms] OR “Prostatic Neoplasms” [MeSH]).

d- Relate the mTORC mechanism to dairy products—Research M4 with dairy products [MeSH Terms] OR “Cultured Milk Products” [MeSH]) AND [“mtor protein [MeSH Terms]” OR mechanistic target of rapamycin complex 1 [MeSH Terms]) OR “TOR Serine-Threonine Kinases” [MeSH]).

FIGURE 1
www.frontiersin.org

Figure 1. Relationship between various searches.

Eligibility and Exclusion Criteria

The research was elaborated according to the following eligibility criteria: Inclusion of review articles and systematic reviews, published in the last 5 years, that restricted research to the human species, male adults, as a target population and also delimiting the research Cancer awareness. All articles were manually analyzed and eligible studies should show association between consumption of dairy products, PC and mTORC1 and/or IGF. Those whose content, despite including MeSH terms defined, deviated from the objective of this review of the literature, because they were out of the subject or because they were repeated. Eligible articles are included in this review of the literature.

Results

As a result of the various surveys, 32 articles were reviewed and systematic reviews divided by the groups (Table 1). Research M1- No review or systematic review with the research was identified in the database using the MeSH terms that relate the consumption of dairy products to PC and to the mechanism of activation of the mTORC1 signaling pathway. Although the search with MeSH terms does not present any publication, it was found that doing a search (Kw) using the keywords (mTORC1) and (prostate cancer) and (milk), and not the MeSH terms, there is a review within the scope of the Work that relates cow's milk to mTOR signaling and promotion and initiation of PC.

TABLE 1
www.frontiersin.org

Table 1. Search Results (Kw–search with keywords and no MeSH terms).

Research M2−9 articles were identified that relate the consumption of dairy products to PC, of which 4 were excluded because they were included in the exclusion criteria. Of these 4 studies, 3 were excluded because they related dairy consumption to other specific cancers and not to PC or cancer in general (5053).

Research M3—With the research, 16 reviews and systematic reviews were identified that relate PC to mTORC1 and IGF mechanisms. These subjects were excluded from the study by 6: 3 because they addressed the issue of PC radiation (5964).

Research M4—With the research, 7 systematic reviews and reviews were identified. In this research the filters “human species, man and cancer” were not used because they did not apply to the subject in question. We excluded 1 review article general (75) for being out of topic.

Discussion

Dairy Products and Prostate Cancer (Research M2)

Of the 5 eligible studies, 1 shows no relationship between dairy intake and cancer. It also concludes that dairy intake reduces the risk of colorectal cancer and is silent about PC (54). The remaining 2 studies associate Dairy Products consumption with increased risk and PC incidence (55, 56). 2 studies conclude that PC prevention strategies go through moderation in consumption of food, meat and dairy products (57, 58).

The first publication analyzed (54) concludes that there was no consistent association between the consumption of dairy products and all specific or non-specific causes of mortality. In this systematic review were identified 408 studies of which excluded 384 by the analysis of the title and abstract not to be included in the theme of the review and excluded another 12 studies after analysis of its content. Of the 13 remnants the majority did not show consistent evidence on the relationship between mortality and milk consumption (54).

An in-vivo study with 2 laboratory guinea pigs showed that the consumption of high doses of milk did not produce PC progression in early stages of tumorigenesis. In addition, the authors conclude that regular milk consumption should not be considered detrimental for patients with early prostatic tumors (83). However, another in vitro study shows that milk can stimulate the growth of prostate cancer cells in culture (84).

Another review and meta-analysis (56) concluded that ingestion of high amounts of dairy products, milk, low-fat milk, cheese, yogurt, and calcium from dairy rather than from supplements or sources Non-dairy products, may increase the overall risk of prostate cancer. This review identified 45 relevant studies, excluding 13 studies per repetition, comparing only 3 types of dairy products, when the objective would be all types of dairy, or for moving away from the theme. The authors also concluded that the divergent results for different types of dairy products and calcium sources studied suggest that other components in dairy products, in addition to fat and calcium, may be related to the increased risk of PC (56).

The high intake of dairy products was also associated with PC with some consistency. However, the same review (55) reports a meta-analysis with 4 cohort studies that shows that there is no evidence between intake of calcium added to dairy products and PC (85). In their conclusions, they are vague in this regard, warning of the need for further studies to clarify the mechanisms involved in carcinogenesis linked to these products (55, 85).

Intake of calcium through consumption of dairy products and not through calcium provided by non-dairy products, showed a positive association with the overall risk of prostate cancer in the studies (55, 8488). However, there was a divergence in results that may be related to other components in dairy products (65). Furthermore, the hypothesis that calcium from dairy products may increase PC risk, does not explain the non-increased risk with ingestion of non-dairy calcium sources (19, 87). Calcium intake is positively associated with aggressive PC while vitamin D intake shows an inverse relationship, and this association varies according to race and BMI (89).

In this review of the literature, 2 studies were also analyzed that are related to PC prevention strategies and both conclude that there is some evidence that moderate food consumption, reduction of dairy intake, Asian or Mediterranean diet may help prevent PC associated with other factors such as healthy habits (57, 58). There is very significant evidence supporting the association between the Mediterranean diet and the reduction of PC risk and disease progression (90, 91).

mTOR, mTORC1, IGF-1, and Prostate Cancer (Research M3)

Six studies conclude that deregulation of mTOR pathway signaling is present in most PC and shows evidence for possible therapy in castration-resistant or hormone-resistant PC with inhibitors of these pathways (6671); 3 studies relate circulating amounts of IGF with PC progression (7274); 1 Study associates positively the metabolic syndrome/IGF and PC incidence (65).

Deregulation of the mTOR signaling pathway is associated with the promotion or progression of PC and evidence for possible PC therapy resistant to castration or hormone-resistant with inhibitors of these pathways(69, 71). Rapamycin was the first mTOR inhibitor discovered and approved for the treatment of cancer. Thus, inhibitors of these pathways may be therapeutic alternatives for PC; However, most are unstable molecules that exhibit toxic effects, and further studies are needed (67, 68, 71). On the other hand, fisetin, a dietary flavonoid, may act as a double inhibitor of the PI3K/AKt and mTORC pathways. It is a significant finding that the activation or overexpression of mTOR signaling is common in tumors with overexpression of Pi3K/Akt (66).

MTOR inhibitors may be a promising therapy in PC that is resistant to conventional hormone therapy (67). The mTOR protein plays a crucial role in this signaling pathway being responsible for the regulation of cell growth and protein synthesis. Changes in this pathway are associated with carcinogenesis, angiogenesis, tumor growth and metastasis, and this deregulation is present in almost 100% of the advanced PCs (69, 92). Preclinical studies demonstrate that the PI3K/Akt/mtORC signaling pathway plays a key role in the progression of castration-resistant PC (68, 70). Recent literature shows that mTORC1 controls the programming in mRNA translation of the genes involved in the initiation and metastasis of PC (9395). Reviews also relate PC to circulating IGF amounts. IGF, essential for physiological growth, may also be implicated in numerous diseases, including cancers. Anabolic signs of IGF-1 may promote the development of tumors through the anti-apoptosis effect and by stimulation of cell proliferation (96, 97). Modulators of this factor, such as IGFBP-6, may be useful in modeling the amount of IGFII (73). Preclinical studies in PC show that the segmentation of IGF receptors may constitute a promising anti-tumor effect (74). The association between obesity/insulin resistance and PC progression and lethality may be mediated through the activation of the GH/IGF1 axis (72). Therapies that inhibit this axis may play a preventive role in the progression of the disease (74). There is a direct correlation between the metabolic syndrome, hyperinsulinemia and elevated levels of IGF and PC(65). A recent meta-analysis of 12 studies found a slightly increased risk for PC incidence (odds ratio 1.38, 95% CI 1.19–1.60) in subjects with higher serum IGF-1 levels. The authors have some limitations, since they only use a single blood collection per patient, the titration was performed only by laboratory methods, and in some patients the stage of disease progression was not known (98). However, epidemiological studies also show that higher levels of circulating IGF-1 within normal ranges are associated with increased risk of developing tumors including PC, colorectal and breast cancer (99). If we analyze the influence of increased mTOR pathway signaling on PC promotion, there is a great deal of clear information and even many revisions that show that the path of therapy may be related to this mechanism. In almost 100% of PC there is deregulation of this signaling pathway (92).

Dairy Products and Increased TOR, PI3 Kinase-AKT Signaling (Research M4)

The 6 eligible publications reflect a positive association between milk consumption and increased mTORC1 signaling. Human milk contains 1.2 g/100ml of milk proteins compared to cow's milk containing 3.5 g/100ml, almost 3 times more branched-chain amino acid proteins (BCAAs) (77, 79, 100102), especially leucine (103). The available BCAAs play a key role in the activation of the mTORC1 complex (104106). Glutamine in milk, 70% more than in meat (107) is also an amino acid with important activation power of mTORC1 (108, 109). In addition, pasteurized cow's milk transfers biologically active exosomal microRNA to the systemic circulation of the consumer that apparently can affect more than 11,000 human genes, including the mTORC1 complex (80). Breast milk has an essential role in regulating growth during the postnatal period of mammals (110) and constitutes a complex bio-fluid that transfers nutritionally important, protective and fundamental substances for the optimal developme nt of the baby (62). However, their intake during adolescence seems to be being called into question. Excess nutrients from dairy products ingested systematically since adolescence, such as glutamine, BCAAs, leucine, palmitic acid, IGF, bioactive exosomal microRNAs promote an over-activation of the mTORC1 complex with consequent increase in transcription, translocation of mRNA, cell growth and proliferation cellular (44, 105, 106, 111113).

Milk may represent the most sophisticated endocrine regulation system for the activation of mTORC1 complex (78) for the supply of BCAAs from milk proteins and exosomal mRNA produced by mammary glands that contribute to the activation of mTORC1 related to Numerous modern diseases (114, 115). Excessively ingested milk may be an epigenetic amplifier of the FTO gene-mediated transcription (79). The FTO gene (association and obesity and fat mass) is assigned a fundamental role in the control of body weight, body composition and energy balance (116). Milk, the most common food introduced from an early age, is not only a food but also represents a sophisticated signaling system that promotes mTORC-mediated growth (78) and has also been shown to stimulate mTORc1-dependent translocation (80). The increased expression of the milk-activated FTO gene leads to mTOR deregulation and increased mRNA translation (117). Individuals with this epigenetic alteration may be more susceptible to milk-mediated FTO activation (79). In addition, there is also a positive correlation between circulating IGF-1 levels and milk consumption. After the meta-analysis, the weighted mean difference in circulating IGF-I level was 13.8 ng/ml (95% confidence interval: 6.1–21.5 ng/ml) comparing the intervention group with the control group (32). However, factors such as insulin, IGF and isolated amino acids do not appear to be sufficient for maximal activation of TORC1 (118). On the other hand, insulin in the presence of amino acids from dairy products can induce a maximal activation of mTORC1 (119). Other reviews analyzed, relate the consumption of dairy products and the activation of the mTORC signaling pathway and conclude that milk consumption during pregnancy can be determinant in the risk of developing diseases of civilization, such as obesity, diabetes, and cancer (76) and therefore the limits of milk consumption during this phase should be reevaluated (120).

The exaggerated increase in western dietary mTORC1 signaling may explain the association between diabetes mellitus (81) and acne (121) with increased fat mass, insulin resistance (122) and early menarche (15). They may also be indicators of over-activation of the mammalian target of rapamycin 1 complex, arterial hypertension (38, 123125).

Dairy, Prostate Cancer, and Increased mTOR Signaling (Research KW)

No review was found with the selection criteria that directly related the incidence of PC with increased signaling of the mTORC pathway induced by dairy products. However, the identified study where the keywords were used and not the MeSH terms (Kw research), relates the impact of cow's milk on mTORC1 signaling on PC initiation and progression (82). PC is dependent on androgen receptors and aberrations in PI3K/Akt-mTORC1 pathways, by excessive signaling. This activation enhances mRNA transcription and distinct phases of PC initiation and progression. Some components of cow's milk, not breast milk, can activate mTORC. Increased intakes of cow's milk, dairy proteins, and estrogens in cow's milk, especially of pregnant cows, may explain the high incidence of PC in modern Western societies. Milk proteins contribute to the increase of branched-chain amino acids (BCAAs—leucine, isoleucine, and valine) and elevated postprandial plasma levels of IGF-1 insulin, which activate mTORC-signaling pathways (82, 126, 127). Higher levels of glucose and ATP may also be implicated in this deregulation (44, 128). However, studies show evidence that only whole milk may be associated with a high incidence of lethal PC (129). The FTO gene is associated with increased PC risk (130, 131). Milk-mediated epigenetic activation of FTO can lead to FTO activation leading to the activation of mTORC1 (65) and possibly related to the onset and metastasis of PC (82, 95). Consumption of dairy products may increase this signaling, since current milk is concentrated in the nutrients that contribute to its over-activation. The activation of mTORC1 depends on available amounts of AAs, specifically BCAAs and leucine, glutamine, IGF, insulin, exosomal micro mRNA, palmitic acid, high glucose levels, and ATP (44, 80, 128). However, it should be clarified which type of dairy and what concentrations in hormones, leucine, IgF, BCAAs required for mTORC activation and synergistic combinations of potentiating nutrients (119). The origin of milk (cow, goat, sheep, and pregnant cows), type of dairy products and amounts of intake may imply different impacts on the increased risk and progression of PC (132). The studies analyzed do not differentiate this question. According to the studies, the impact on risk may also be dependent on the time at which dairy consumption is higher, and in the postnatal period, the benefits of breast milk consumption are unequivocal, whereas during adolescence the consumption of milk from cow may contribute to the increased risk of PC (13). Exosomal mRNA activity in cell communication may lead to different impacts of different types of milk and whether or not mammalian milks will have their own characteristics within each species. Can the microRNAs contained in cow's milk induce this change in other mammals?

Some polymorphisms may also be decisive in PC expression, such as FTO (65, 79). Is this increase in signaling dependent on some other polymorphism?

Eligible studies in this research have some limitations. The definition of search criteria is very extended, there was substantial heterogeneity among studies of non-fermented milk consumption in relation to mortality from all causes. Nor have any reviews considered the different types of dairy products, diverging results for types of dairy products and sources of calcium suggest that other components of dairy than fat and calcium may increase prostate cancer risk.

Some authors conclude that moderate food consumption, reduction of dairy products can prevent prostate cancer but also harbors additional beneficial effects on general health. However, moderate consumption and the kind of dairy Products are not defined. No review correlates with other concomitant eating habits, genetic factors, or lifestyle.

Conclusions

Studies reviews selected through defined research criteria that directly relate to dairy consumption and PC are contradictory, inconsistent, and omitted in possible justifications or responsible mechanisms. Nevertheless, most of the reviews point to a positive association between milk consumption and the incidence or increase of PC risk. However, there is strong evidence in the literature (not reviews) that associates dairy consumption and PC (91) and disease progression (82, 133), and possibly initialization (82). Through this review of the literature we understand the different mechanisms triggered by nutrients contained in milk and derivatives that may lead to an increased risk of prostate cancer in its consumers. However, further studies are needed to clarify which detrimental derivatives and which quantities are required for tumor progression and/or initiation. A better understanding of cancer and this signaling pathway may lead to the development of more effective and tumor-specific drugs and to define preventive measures of the tumor with a higher incidence in man and other types of cancer, such as breast cancer (67).

In conclusion, according to the analysis of the available information, it is possible to establish a relationship between the consumption of dairy products and the progression of PC and possibly its initiation and should therefore be reduced or minimized in the diet of men.

Author Contributions

AV conceived the study, participated in its design and coordination, draft, and authored the manuscript. PR participated in the study design, interpretation of the data, and helped to draft manuscript revisions. TS and PN were responsible for scientific writing and manuscript editing.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations

PC, Prostate Cancer; mTORC1, Mammalian Target of Rapamycin Complex; P13K, phosphatidylinositol 3-kinase; Akt, Proteins kinase; IGF 1, Insulin-like Growth Factor; BCAAs, Branched chain amino acids; T2DM, Type 2 Diabetes Mellitus; Aas, Amino acids; BMI, Body Mass Index.

References

1. Filippou P, Ferguson JE III, Nielsen ME. Epidemiology of prostate and testicular cancer. Semin Intervent Radiol. (2016) 33:182–5. doi: 10.1055/s-0036-1586146

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Hassanipour-Azgomi S, Mohammadian-Hafshejani A, Ghoncheh M, Towhidi F, Jamehshorani S, Salehiniya H Incidence and mortality of prostate cancer and their relationship with the Human Development Index worldwide. Prostate Int. (2016) 4:118–24. doi: 10.1016/j.prnil.2016.07.001

PubMed Abstract | CrossRef Full Text | Google Scholar

3. International Agency for Research-Global Cancer Observatory. Available online at: http://globocan.iarc.fr/old/FactSheets/cancers/prostate-new.asp (accessed November, 2016).

Google Scholar

4. Khazaei S, Rezaeian S, Ayubi E, Gholamaliee B, Pishkuhi MA, Khazaei S, et al. Global prostate cancer incidence and mortality rates according to the human development index. Asian Pac J Cancer Prev. (2016) 17:3793–6. doi: 10.7314/APJCP.2016.17.S3.253

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Nesvadba M, Cmorej P, Mamova A, Slowik O. The incidence, mortality and risk factors of prostate cancer. Epidemiol Mikrobiol Imunol. (2016) 65:211–4.

PubMed Abstract | Google Scholar

6. Sonn GA, Aronson W, Litwin MS. Impact of diet on prostate cancer: a review. Prostate Cancer Prostatic Dis. (2005) 8:304–10. doi: 10.1038/sj.pcan.4500825

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Marshall JR. Diet and prostate cancer prevention. World J Urol. (2012) 30:157–65. doi: 10.1007/s00345-011-0810-0

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Ferrís-Tortajada J, Berbel-Tornero O, García-Castell J, Ortega-García JA, López-Andreu JA. Factores dietéticos asociados al cáncer de próstata. Beneficios de la dieta mediterrânea. Actas Urol Esp. (2012) 36:239–245. doi: 10.1016/j.acuro.2011.08.002

CrossRef Full Text | Google Scholar

9. Gao X, La Valley MP, Tucker KL. Prospective studies of dairy produts and calcium intakes and prostate cancer: a meta-analysis. J Natl Cancer Inst. (2005) 97:1768–77. doi: 10.1093/jnci/dji402

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Qin LQ, Xu JY, Wang PY, Kaneko T, Hoshi K, Sato A. Milk consumption is a risk factor for prostatic cancer: meta-analysis of case-control studies. Nutr Cancer. (2004) 48:22–7. doi: 10.1207/s15327914nc4801_4

CrossRef Full Text | Google Scholar

11. Ma RW, Chapman K. A systematic review of the effect of diet in prostate cancer prevention and treatment. J Hum Nutr Diet. (2009) 22:187–99. doi: 10.1111/j.1365-277X.2009.00946.x

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Pauwels EK. The protective effect of the Mediterranean diet: focus on cancer and cardiovascular risk. Med Princ Pract. (2011) 20:103–11. doi: 10.1159/000321197

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Torfadottir JE, Steingrimsdottir L, Mucci L, Aspelund T, Kasperzyk JL, Olafsson O, et al. Milk intake in early life and risk of advanced prostate cancer. Am J Epidemiol. (2012) 175:144–53. doi: 10.1093/aje/kwr289

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Wiley AS. Milk intake and total dairy consumption: associations with early menarche in NHANES 1999-2004. PLoS ONE. (2011) 6:e14685. doi: 10.1371/journal.pone.0014685

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Wiley AS. Dairy and milk consumption and child growth: is BMI involved? An analysis of NHANES 1999-2004. Am J Hum Biol. (2010) 22:517–25. doi: 10.1002/ajhb.21042

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Socha P, Grote V, Gruszfeld D, Janas R, Demmelmair H, Closa-Monasterolo R, et al. Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr. (2011) 94 (Suppl. 6):1776S−84S. doi: 10.3945/ajcn.110.000596

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Lu W, Chen H, Niu Y, Wu H, Xia D, Wu Y. Dairy products intake and cancer mortality risk: a meta-analysis of 11 population-based cohort studies. Nutr J. (2016) 15:91. doi: 10.1186/s12937-016-0210-9

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Grover PL, Martin FL. The initiation of breast and prostate cancer. Carcinogenesis. (2002) 23:1095–102. doi: 10.1093/carcin/23.7.1095

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Tjønneland A, et al. Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition. Br J Cancer. (2008) 98:1574–8. doi: 10.1038/sj.bjc.6604331

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Mucci LA, Signorello LB, Adami HO. Prostate cancer. In: HO Adami, D Hunter, and D Trichopoulos editors. Textbook of Cancer Epidemiology, 2nd edn. Oxford: Oxford University Press (2008). p. 517–54. doi: 10.1093/acprof:oso/9780195311174.003.0020

CrossRef Full Text | Google Scholar

21. Stacewicz-Sapuntzakis M, Borhakur G, Burns JL, Bowen PE. Correlations of dietary patterns with prostate health. Mol Nutr Food Res. (2008) 52:114–30. doi: 10.1002/mnfr.200600296

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Hori S, Butter E, McLoughlin J. Prostate cancer and diet: food for thouht? BJU Int. (2011) 107:1348–59. doi: 10.1111/j.1464-410X.2010.09897.x

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Surveillance Epidemiology and End Results Program. SEER Stat Facts Sheets: Prostate Cancer. National Cancer Institute. (2013). Available online at: http://seer.cancer.gov/statfacts/html/prost.html (accessed February, 2017).

24. June M., Chan, Erin L., Van Blarigan, Stacey A. Kenfield. What should we tell prostate cancer patients about (secondary) prevention? Curr Opin Urol. (2014) 24:318–23. doi: 10.1097/MOU.0000000000000049

CrossRef Full Text | Google Scholar

25. Liao RS, Ma S, Miao L, Li R, Yin Y, Raj GV. Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Transl Androl Urol. (2013) 2:187–96. doi: 10.3978/j.issn.2223-4683.2013.09.07

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Malekinejad H, Rezabakhsh A. Hormones in dairy foods and their impact on public health - a narrative review article. Iran J Public Health. (2015) 44:742–58.

PubMed Abstract | Google Scholar

27. Hansel W, Hixon J, SheMeSH M, Tobey D. Concentrations and activities of prostaglandins of the F series in bovine tissue, blood and milk. J Dairy Sci. (1976) 59:1353–65. doi: 10.3168/jds.S0022-0302(76)84368-8

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Atroshi F, Rizzo A, Osterman T, Parantainen J. Free fatty acids and lipid peroxidation in normal and mastitic bovine milk. Zentralbl Veterinarmed. (1989) A 36:321–30. doi: 10.1111/j.1439-0442.1989.tb00736.x

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Collier RJ, Miller MA, Hildebrandt JR, Torkelson AR, White TC, Madsen KS, et al. Factors affecting insulin-like growth factor-I concentration in bovine milk. J Dairy Sci. (1991) 74:2905–11. doi: 10.3168/jds.S0022-0302(91)78473-7

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Chaves J, Saif MW. IGF system in cancer: from bench to clinic. Anticancer Drugs. (2011) 22:206–12. doi: 10.1097/CAD.0b013e32834258a1

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Fürstenberger G, Senn HJ. Insulin-like growth factors and cancer. Lancet Oncol. (2002) 3:298–302. doi: 10.1016/S1470-2045(02)00731-3

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Qin LQ, He K, Xu JY. Milk consumption and circulating insulin-like growth factor-I level: a systematic literature review. Int J Food Sci Nutr. (2009) 60 (Suppl. 7):330–40. doi: 10.1080/09637480903150114

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Thorning TK, Raben A, Tholstrup T, Soedamah-Muthu SS, Givens I, Astrup A. Milk and dairy products: good or bad for human health? An assessment of the totality of scientific evidence. Food Nutr Res. (2016) 60:32527. doi: 10.3402/fnr.v60.32527

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Chen X, Cheng H, Pan T, Liu Y, Su Y, Ren C, et al. mTOR regulate EMT through RhoA and Rac1 pathway in prostate cancer. Mol Carcinog. (2015) 54:1086–95. doi: 10.1002/mc.22177

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Mirkheshti N, Park S, Jiang S, Cropper J, Werner SL, Song CS, et al. Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. Oncotarget. (2016) 7:62240–54. doi: 10.18632/oncotarget.11404

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Cortot A, Armand J-P, Soria J-C. Les inhibiteurs de la voie PI3 kinase-AKTmTOR. Bull Cancer. (2006) 93:19–26.

Google Scholar

37. Shaw RJ, Cantley LC. Ras, PI (3)K and mTOR signalling controls tumour cell growth. Nature. (2006) 441:424–30. doi: 10.1038/nature04869

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. (2012) 13:1886–918. doi: 10.3390/ijms13021886

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Cargnello M, Tcherkezian J, Roux PP. The expanding role of mTOR in cancer cell growth and proliferation. Mutagenesis. (2015) 30:169–76. doi: 10.1093/mutage/geu045

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Vo BT, Morton D Jr, Komaragiri S, Millena AC, Leath C, Khan SA. TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. Endocrinology. (2013) 154:1768–79. doi: 10.1210/en.2012-2074

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Wozney JL, Antonarakis ES. Growth factor and signaling pathways and their relevance to prostate cancer therapeutics. Cancer Metastasis Rev. (2014) 33:581–94. doi: 10.1007/s10555-013-9475-z

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Majumder PK, Sellers WR: Akt-regulated pathways in prostate cancer. Oncogene. (2005) 24:7465–74. doi: 10.1038/sj.onc.1209096

CrossRef Full Text | Google Scholar

43. Wang X, Proud CG. mTORC1 signalling: what we still don't know. J Mol Cell Biol. (2011) 3:206–20. doi: 10.1093/jmcb/mjq038

CrossRef Full Text | Google Scholar

44. Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab. (2012) 302:E1329–42. doi: 10.1152/ajpendo.00525.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Gallinetti J, Harputlugil E, Mitchell JR. Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J. (2013) 449:1–10. doi: 10.1042/BJ20121098

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Meijer AJ, Lorin S, Blommaart EF, Codogno P. Regulation of autophagy by amino acids and MTOR-dependent signal transduction. Amino Acids. (2015) 47:2037–63. doi: 10.1007/s00726-014-1765-4

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Yin Y, Hua H, Li M, Liu S, Kong Q, Shao T, et al. mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. Cell Res. (2016) 26:46–65. doi: 10.1038/cr.2015.133

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Buts JP. Bioactive factors in milk. Arch Pediatr. (1998) 5:298–306. doi: 10.1016/S0929-693X(97)89374-8

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Martemucci G, D'Alessandro AG. Progress in nutritional and health profile of milk and dairy products: a novel drug target. Endocr Metab Immune Disord Drug Targets. (2013) 13:209–33. doi: 10.2174/18715303113136660045

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Chen M, Sun Q, Giovannucci E, Mozaffarian D, Manson JE, Willett WC, et al. Dairy consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. BMC Med. (2014) 12:215. doi: 10.1186/s12916-014-0215-1

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Ralston RA, Truby H, Palermo CE, Walker KZ. Colorectal cancer and nonfermented milk, solid cheese, and fermented milk consumption: a systematic review and meta-analysis of prospective studies. Crit Rev Food Sci Nutr. (2014) 54:1167–79. doi: 10.1080/10408398.2011.629353

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Forouhi NG. Association between consumption of dairy products and incident type 2 diabetes-insights from the European Prospective Investigation into Cancer study. Nutr Rev. (2015) 73 (Suppl.)1:15–22. doi: 10.1093/nutrit/nuv018

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Franko B, Vaillant M, Recule C, Vautrin E, Brion JP, Pavese P. Lactobacillus paracasei endocarditis in a consumer of probiotics. Med Mal Infect. (2013) 43:171–3. doi: 10.1016/j.medmal.2013.01.007

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Larsson SC, Crippa A, Orsini N, Wolk A, Michaëlsson K. Milk consumption and mortality from all causes, cardiovascular disease, and cancer: a systematicreview and meta-analysis. Nutrients. (2015) 7:7749–63. doi: 10.3390/nu7095363

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Abid Z, Cross AJ, Sinha R. Meat, dairy, and cancer. Am J Clin Nutr. (2014) 100 (Suppl. 1):386S−93S. doi: 10.3945/ajcn.113.071597

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Aune D, Navarro Rosenblatt DA, Chan DS, Vieira AR, Vieira R, Greenwood DC, et al. Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Am J Clin Nutr. (2015) 101:87–117. doi: 10.3945/ajcn.113.067157

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Schmitz-Dräger BJ, Lümmen G, Bismarck E, Fischer C. Prevention strategies for prostate cancer. Minerva Urol Nefrol. (2012) 64:225–31.

PubMed Abstract | Google Scholar

58. Schmitz-Dräger BJ, Sahin S, Lümmen G, Bismarck E, Fischer C. Mitglieder des Arbeitskreises Prävention, Umwelt und Komplementärmedizin (PUK). [Nutritional prevention of urological tumours]. Aktuelle Urol. (2014) 45:281–5. doi: 10.1055/s-0034-1383645

CrossRef Full Text | Google Scholar

59. Alcorn S, Walker AJ, Gandhi N, Narang A, Wild AT, Hales RK, et al. Molecularly targeted agents as radiosensitizers in cancer therapy-focus on prostate cancer. Int J Mol Sci. (2013) 14:14800–32. doi: 10.3390/ijms140714800

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Chang L, Graham PH, Hao J, Bucci J, Cozzi PJ, Kearsley JH, et al. Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev. (2014) 33:469–96. doi: 10.1007/s10555-014-9493-5

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Mooney D, Paluri R, Mehta A, Goyal J, Sonpavde G. Update in systemic therapy of urologic malignancies. Postgrad Med. (2014) 126:44–54. doi: 10.3810/pgm.2014.01.2724

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Alsaweed M, Lai CT, Hartmann PE, Geddes DT, Kakulas F. Human milk cells contain numerous miRNAs that may change with milk removal and regulate multiple physiological processes. Int J Mol Sci. (2016) 17:956. doi: 10.3390/ijms17060956

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Quan H, Tang H, Fang L, Bi J, Liu Y, Li H. IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and cancer risk: a meta-analysis. Cell Biochem Biophys. (2014) 69:169–78. doi: 10.1007/s12013-013-9784-4

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Panagiotou OA, Ioannidis JP. Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists. J Clin Epidemiol. (2012) 65:740–7. doi: 10.1016/j.jclinepi.2012.01.008

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Conteduca V, Di Lorenzo G, Bozza G, Ardito R, Aieta M. Metabolic syndrome as a peculiar target for management of prostate cancer patients. Clin Genitourin Cancer. (2013) 11:211–20. doi: 10.1016/j.clgc.2013.04.009

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Adhami VM, Syed DN, Khan N, Mukhtar H. Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem Pharmacol. (2012) 84:1277–81. doi: 10.1016/j.bcp.2012.07.012

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Burgio SL, Fabbri F, Seymour IJ, Zoli W, Amadori D, De Giorgi U. Perspectives on mTOR inhibitors for castration-refractory prostate cancer. Curr Cancer Drug Targets. (2012) 12:940–9. doi: 10.2174/156800912803251234

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer. (2013) 20:R83–99. doi: 10.1530/ERC-12-0394

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl. (2014) 16:378–86. doi: 10.4103/1008-682X.122876

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Tang KD, Ling MT. Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition. Curr Med Chem. (2014) 21:3048–56. doi: 10.2174/0929867321666140414100127

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Chang L, Graham PH, Ni J, Hao J, Bucci J, Cozzi PJ, Li Y. Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. Crit Rev Oncol Hematol. (2015) 96:507–17. doi: 10.1016/j.critrevonc.2015.07.005

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Aggarwal RR, Ryan CJ, Chan JM. Insulin-like growth factor pathway: a link between androgen deprivation therapy (ADT), insulin resistance, and disease progression in patients with prostate cancer? Urol Oncol. (2013) 31:522–30. doi: 10.1016/j.urolonc.2011.05.001

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Bach LA, Fu P, Yang Z. Insulin-like growth factor-binding protein-6 and cancer. Clin Sci. (2013) 124:215–29. doi: 10.1042/CS20120343

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Heidegger I, Massoner P, Sampson N, Klocker H. The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer. Cancer Lett. (2015) 367:113–21. doi: 10.1016/j.canlet.2015.07.026

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Lei J, Feng D, Zhang Y, Zhao FQ, Wu Z, San Gabriel A, et al. Nutritional and regulatory role of branched-chain amino acids in lactation. Front Biosci. (2012) 17:2725–39. doi: 10.2741/4082

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Melnik BC, John SM, Schmitz G. Milk consumption during pregnancy increases birth weight, a risk factor for the development of diseases of civilization. J Transl Med. (2015) 13:13. doi: 10.1186/s12967-014-0377-9

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Melnik BC, John SM, Plewig G. Acne: risk indicator for increased body mass index and insulin resistance. Acta Derm Venereol. (2013) 93:644–9. doi: 10.2340/00015555-1677

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Melnik BC, John SM, Schmitz G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr J. (2013) 12:103. doi: 10.1186/1475-2891-12-103

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Melnik BC. Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases. J Transl Med. (2015) 13:385. doi: 10.1186/s12967-015-0746-z

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Melnik BC. Milk- a nutrient system of mammalian evolution promoting mTORC1-dependent translation. Int J Mol Sci. (2015) 16:17048–87. doi: 10.3390/ijms160817048

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Melnik BC. The pathogenic role of persistent milk signaling in mTORC1- and milk microRNA-driven type 2 diabetes mellitus. Curr Diabetes Rev. (2015) 11:46–62. doi: 10.2174/1573399811666150114100653

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Melnik BC, John SM, Carrera-Bastos P, Cordain L. The impact of cow's milk- mediated mTORC1-signaling in the initiation and progression of prostate cancer. Nutr Metab. (2012) 9:74. doi: 10.1186/1743-7075-9-74

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Bernichtein S, Pigat N, Capiod T, Boutillon F, Verkarre V, Camparo P, et al. Goffin High milk consumption does not affect prostate tumor progression in two mouse models of benign and neoplastic lesions. PLoS ONE. (2015) 10:e0125423. doi: 10.1371/journal.pone.0125423

CrossRef Full Text | Google Scholar

84. Tate PL, Bibb R, Larcom LL. Milk stimulates growth of prostate cancer cells in culture. Nutr Cancer. (2011) 63:1361–6. doi: 10.1080/01635581.2011.609306

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Huncharek M, Muscat J, Kupelnick B. Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer. (2008) 60:421–41. doi: 10.1080/01635580801911779

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Koh KA, Sesso HD, Paffenbarger RS, Lee IM. Dairy products, calcium and prostate cancer risk. Br J Cancer. (2006) 95:1582–5. doi: 10.1038/sj.bjc.6603475

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Park Y, Leitzmann MF, Subar AF, Hollenbeck A, Schatzkin A. Dairy food, calcium, and risk of cancer in the NIH-AARP Diet and Health Study. Arch Intern Med. (2009) 169:391–401. doi: 10.1001/archinternmed.2008.578

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Newmark HL, Heaney RP. Dairy products and prostate cancer risk. Nutr Cancer. (2010) 62:297–9. doi: 10.1080/01635580903407221

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Batai K, Murphy AB, Ruden M, Newsome J, Shah E, Dixon MA, et al. Race and BMI modify associations of calcium and vitamin D intake with prostate cancer. BMC Cancer. (2017) 17:64. doi: 10.1186/s12885-017-3060-8

PubMed Abstract | CrossRef Full Text | Google Scholar

90. López-Guarnido O, Álvarez-Cubero MJ, Saiz M, Lozano D, Rodrigo L, Pascual M, et al. Mediterranean diet adherence and prostate cancer risk. Nutr Hosp. (2014) 31:1012–9. doi: 10.3305/nh.2015.31.3.8286

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Mandair D, Rossi RE, Pericleous M, Whyand T, Caplin ME. Prostate cancer and the influence of dietary factors and supplements: a systematic review. Nutr Metab. (2014) 11:30. doi: 10.1186/1743-7075-11-30

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. (2010) 18:11–22. doi: 10.1016/j.ccr.2010.05.026

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Clohessy JG, Reschke M, Pandolfi PP. Found in translation of mTOR signaling. Cell Res. (2012) 22:1315-8. doi: 10.1038/cr.2012.85

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. (2012) 485:109–16. doi: 10.1038/nature11083

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. (2012) 485:55–61. doi: 10.1038/nature10912

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nature Rev Cancer. (2004) 4:505–18. doi: 10.1038/nrc1387

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Foulstone E, Prince S, Zaccheo O, Burns JL, Harper J, Jacobs C, et al. Insulin-like growth factor ligands, receptors, and binding proteins in cancer. J Pathol. (2005) 205:145–53. doi: 10.1002/path.1712

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Roddam AW, Allen NE, Appleby P, Key TJ, Ferrucci L, Carter HB, et al. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann Internal Med. (2008) 149:461–71. doi: 10.7326/0003-4819-149-7-200810070-00006

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. (2008) 8:915–28. doi: 10.1038/nrc2536

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Kim J, Guan KL. Amino acid signaling in TOR activation. Ann Rev Biochem. (2011) 80:1001–32. doi: 10.1146/annurev-biochem-062209-094414

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Efeyan A, Sabatini DM. Nutrients and growth factors in mTORC1 activation. Biochem Soc Trans. (2013) 41:902–5. doi: 10.1042/BST20130063

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Kim S, Buel GR, Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells. (2013) 35:463–73. doi: 10.1007/s10059-013-0138-2

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Millward DJ, Layman DK, Tomé D, Schaafsma G. Protein quality assessment: impact of expanding understanding of protein and amino acid needs for optimal health. Am J Clin Nutr. (2008) 87:1576S–81S. doi: 10.1093/ajcn/87.5.1576S

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. (2009) 296:E592–602. doi: 10.1152/ajpendo.90645.2008

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Jewell JL, Guan KL. Nutrient signaling to mTOR and cell growth. Trends Biochem Sci. (2013) 38:233–42. doi: 10.1016/j.tibs.2013.01.004

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Oshiro N, Rapley J, Avruch J. Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging. J Biol Chem. (2014) 289:2658–74. doi: 10.1074/jbc.M113.528505

PubMed Abstract | CrossRef Full Text | Google Scholar

107. Lenders CM, Liu S, Wilmore DW, Sampson L, Dougherty LW, Spiegelman D, et al. Evaluation of a novel food composition database that includes glutamine and other amino acids derived from gene sequencing data. Eur J Clin Nutr. (2009) 63:1433–9. doi: 10.1038/ejcn.2009.110

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Xu G, Kwon G, Cruz WS, Marshall CA, McDaniel ML. Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes. (2001) 50:353–60. doi: 10.2337/diabetes.50.2.353

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Lorin S, Tol MJ, Bauvy C, Strijland A, Poüs C, Verhoeven AJ, et al. Glutamate dehydrogenase contributes to leucine sensing in the regulation of autophagy. Autophagy. (2013) 9:850–60. doi: 10.4161/auto.24083

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Modepalli V, Kumar A, Hinds LA, Sharp JA, Nicholas KR, Lefevre C. Differential temporal expression of milk miRNA during the lactation cycle of the marsupial tammar wallaby (Macropus eugenii). BMC Genomics. (2014) 15:1012. doi: 10.1186/1471-2164-15-1012

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Wang X, Yu W, Nawaz A, Guan F, Sun S, Wang C. Palmitate induced insulin resistance by PKCtheta-dependent activation of mTOR/S6K pathway in C2C12 myotubes. Exp Clin Endocrinol Diabetes. (2010) 118:657–61. doi: 10.1055/s-0030-1252069

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Izumi H, Kosaka N, Shimizu T, Sekine K, Ochiya T, Takase M. Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. J Dairy Sci. (2012) 95:4831–41. doi: 10.3168/jds.2012-5489

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Izumi H, Tsuda M, Sato Y, Kosaka N, Ochiya T, Iwamoto H, et al. Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. J Dairy Sci. (2015) 98:2920–33. doi: 10.3168/jds.2014-9076

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. (2011) 12:21–35. doi: 10.1038/nrm3025

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Dey N, Das F, Ghosh-Choudhury N, Mandal CC, Parekh DJ, Block K, et al. MicroRNA-21 governs TORC1 activation in renal cancer cell proliferation and invasion. PLoS ONE. (2012) 7:e37366. doi: 10.1371/journal.pone.0037366

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Sebert S, Salonurmi T, Keinänen-Kiukaanniemi S, Savolainen M, Herzig KH, Symonds ME, et al. Programming effects of FTO in the development of obesity. Acta Physiol. (2014) 210:58–69. doi: 10.1111/apha.12196

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc Natl Acad Sci USA. (2013) 110:2557–62. doi: 10.1073/pnas.1222796110

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA. (2005) 102:14238–43. doi: 10.1073/pnas.0506925102

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Dennis MD, Baum JI, Kimball SR, Jefferson LS. Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. J Biol Chem. (2011) 286:8287–96. doi: 10.1074/jbc.M110.209171

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Dodd JM, McPhee AJ, Turnbull D, Yelland LN, Deussen AR, Grivell RM, et al. The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on neonatal health outcomes: the LIMIT randomized trial. BMC Med. (2014) 12:163. doi: 10.1186/s12916-014-0163-9

CrossRef Full Text | Google Scholar

121. Melnik B. Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet. Dermatoendocrinology. (2012) 4:20–32. doi: 10.4161/derm.19828

PubMed Abstract | CrossRef Full Text | Google Scholar

122. Halvorsen JA, Vleugels RA, Bjertness E, Lien L. A population-based study of acne and body mass index in adolescents. Arch Dermatol. (2012) 148:131–2. doi: 10.1001/archderm.148.1.131

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Harlan SM, Guo DF, Morgan DA, Fernandes-Santos C, Rahmouni K. Hypothalamic mTORC1 signalling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. (2013) 17:599–606. doi: 10.1016/j.cmet.2013.02.017

CrossRef Full Text | Google Scholar

124. Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci. (2012) 4:941–52. doi: 10.2741/s310

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X, et al. Mammalian target of rapamycin (mTor) mediates tau protein dyshomeostasis: implication for Alzheimer disease. J Biol Chem. (2013) 288:15556–70. doi: 10.1074/jbc.M112.435123

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Ding M, Bruick RK, Yu Y. Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling. Nat Cell Biol. (2016) 18:319–27. doi: 10.1038/ncb3311

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, et al. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science. (2015) 347:194–8. doi: 10.1126/science.1259472

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. (2008) 320:1496–1501. doi: 10.1126/science.1157535

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Song Y, Chavarro JE, Cao Y, Qiu W, Mucci L, Sesso HD, et al. Whole milk intake is associated with prostate cancer-specific mortality among US male physicians. J Nutr. (2013) 143:189–96. doi: 10.3945/jn.112.168484

CrossRef Full Text | Google Scholar

130. Machiela MJ, Lindström S, Allen NE, Haiman CA, Albanes D, Barricarte A, et al. Association of type 2 diabetes susceptibility variants with advanced prostate cancer risk in the Breast and Prostate Cancer Cohort Consortium. Am J Epidemiol. (2012) 176:1121–9. doi: 10.1093/aje/kws191

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Lewis SJ, Murad A, Chen L, Davey Smith G, Donovan J, Palmer T, et al. Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk. PLoS ONE. (2010) 5:e13485. doi: 10.1371/journal.pone.0013485

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Gao Y, Gartenhaus RB, Lapidus RG, Hussain A, Zhang Y, Wang X, et al. Differential IKK/NF-κB activity is mediated by TSC2 through mTORC1 in PTEN-null prostate cancer and tuberous sclerosis complex tumor cells. Mol Cancer Res. (2015) 13:1602–14. doi: 10.1158/1541-7786.MCR-15-0213

PubMed Abstract | CrossRef Full Text | Google Scholar

133. Park SW, Kim JY, Kim YS, Lee SJ, Lee SD, Chung MK. A milk protein, casein, as a proliferation promoting factor in prostate cancer cells. World J Mens Health. (2014) 32:76–82. doi: 10.5534/wjmh.2014.32.2.76

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: prostate cancer, dairy products, milk, mTORC, Signaling of mTOR, IGF-1, BCAAs, cancer prevention

Citation: Vasconcelos A, Santos T, Ravasco P and Neves PM (2019) Dairy Products: Is There an Impact on Promotion of Prostate Cancer? A Review of the Literature. Front. Nutr. 6:62. doi: 10.3389/fnut.2019.00062

Received: 08 October 2018; Accepted: 17 April 2019;
Published: 14 May 2019.

Edited by:

Marilia Seelaender, University of São Paulo, Brazil

Reviewed by:

Miguel Luiz Batista Júnior, University of Mogi das Cruzes, Brazil
Silvia Busquets, University of Barcelona, Spain

Copyright © 2019 Vasconcelos, Santos, Ravasco and Neves. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Pedro Miguel Neves, pedrompneves@gmail.com