The Impact of Cow's Milk-mediated mTORC1-signaling in the Initiation and Progression of Prostate Cancer

Bodo C Melnik; Swen M John; Pedro Carrera-Bastos; Loren Cordain

Disclosures

Nutr Metab. 2012;9(74) 

In This Article

Conclusion

Routine cow's milk consumption of another species` milk is an evolutionary novel dietary behavior that has the potential to alter human life history parameters and may have long-term adverse health effects.[109] Historically, the advantage of cow's milk consumption has been associated with reduced infant mortality, improved fertility, increased BMI in children, earlier onset of menarche and increased linear growth during adolescence.[105,106,109] However, these at first glance "beneficial" effects may become adverse effects later in life, especially in Western populations with a higher life expectancy. The clinical manifestation of PCa is a disease of the elderly. However, the initiation phase of PCa may begin as early as fetal growth.

Our understanding of mammalian milk has changed from a "simple food" to a species-specific endocrine signaling system. Milk's functionality depends on its stimulation of the nutrient-sensitive kinase mTORC1, the critical hub regulating cell growth, proliferation, autophagy and metabolic programming. Increased cow's milk and dairy protein consumption during pregnancy, the period of postnatal infant formula feeding and milk/dairy protein consumption in childhood, adolescence as well as adulthood may promote and maintain abnormally high mTORC1 signaling modifying physiological signaling and mRNA patterns required for adequate tissue morphogenesis and programming resulting in long-term adverse effects on prostate health. Dairy protein-derived activation of mTORC1 signaling may disturb most sensitive "windows" of mTORC1-dependent metabolic programming and autophagy regulation thereby upsetting developmental programming and regular differentiation steps of the prostate gland (Figure 4B). This line of thought may explain the observed cancer-protective effect of prolonged breast-feeding, which ensures the physiological mTORC1-signaling axis provided by human milk. Increased mTORC1-signaling due to cow's milk consumption during puberty may explain the association between frequent cow's milk consumption during adolescence and higher risk of aggressive PCa in adulthood.[30,266]

Sufficient evidence has accumulated to justify the rejection of the "high dairy calcium –low vitamin D-hypothesis" of PCa,[38] whereas the intrinsic signaling capability of milk proteins along with orally bioavailable estrogen metabolites present in milk from pregnant cows represents a more likely explanation for the role of dairy consumption in the development and progression of PCa in Western countries.[6,10,42] As mTORC1-mediated cow's milk signaling shares the same downstream pathways as oncogenic mTORC1 signaling of prostate epithelial cells with growth-promoting genetic aberrations, increased intake of cow's milk and dairy proteins may exaggerate already increased mTORC1 signaling of PCa cells. Thus, cow's milk is not a simple nutrient but an endocrinological effector that provides a pro-survival and anti-autophagy tissue environment promoting the initiation and progression of PCa (Figure 5). In contrast, plant-based dietary regimens are associated with reduced intake of insulinotropic and IGF-1 elevating amino acids as well as cow's milk-derived estrogens and in contrast increase the uptake of potential cancer-preventive natural mTORC1 inhibitors. Hormonal ablation therapy (ADT), metformin treatment, natural mTORC1 inhibitors and targeted therapy with synthetic mTORC1 inhibitors just share a common mode of action: the attenuation of increased mTORC1 activity, which is increased by high milk and dairy protein consumption.

In 1994, Ross and Henderson[267] have asked: "Do diet and androgens alter prostate cancer risk via a common etiologic pathway?" Today, this question may be well explained by androgen- and milk-mediated synergisms in prostate mTORC1 signaling.[97] From an evolutionary perspective it can be concluded that the persistent "abuse" of the growth-promoting signaling system of bovine milk by humans over their entire life span maintains the most important hallmark of cancer biology, i.e., sustained proliferative signaling.[102] The magnitude of mTORC1 signaling of Western diet appears to be much higher than that of Paleolithic diets,[133] which are less insulinotropic, provide lower glycemic load and exclude the intake of cow's milk proteins.[268–271] In the 1930s leaders of pediatrics were convinced that human breast milk is "just food".[272] According to this simplified misconception of milk's biology no further efforts were undertaken to explore milk's growth-promoting signal transduction pathways, allowing the widespread introduction of cow's milk-based infant formula feeding. Subsequent evidence has clearly demonstrated that cow's milk-based infant formula substantially exceeds the insulin, IGF-1 and leucine serum concentrations of formula-fed infants in comparison to breast-fed infants.[110–113] Daily intakes of 500 ml cow's milk for children are still routinely recommended by leading pediatricians.[158] This advice means that one third of daily total protein intake (recommendation 56 g) in the age-range for 14–18 year-old boys will be administered in form of growth-promoting signaling proteins and not by structural proteins like meat or fish. Because adolescence represents a most critical mTORC1-dependent period of prostate differentiation and the subsequent increased risk for PCa,[30] the medical community urgently needs to re-evaluate dietary milk recommendations. Dietary recommendations for children and adolescents require nutrient intakes, which allow an adequate and undisturbed period for prostate morphogenesis and sexual maturation of the prostate gland. In this context, it is of serious concern, that increasing numbers of adolescents and young men consume 60 to 80 g of highly insulinotropic whey protein concentrates daily to gain muscle mass.[273] Thus, future dietary studies should clarify the impact of increased cow's milk protein intake upon early steps of prostate morphogenesis and differentiation. It will become important in future experimental work to define safe upper limits for long-term milk and dairy intake for the prevention of the most common dairy-promoted cancer in men.

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