The impact of cow’s milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer

Nutrition & Metabolism (Impact Factor: 3.26). 08/2012; 9(1):74. DOI: 10.1186/1743-7075-9-74
Source: PubMed


Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensive kinase mTORC1 is upregulated in nearly 100 % of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow's milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milkmediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow's milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk's fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow's milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow's milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow's milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairypromoted cancer in men of Western societies.

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    • "mTORC1 steers prostate cancer (PCa) initiation and metastasis [69]. Accumulating evidence links PCa initiation and progression to increased milk protein consumption and milk-mediated activation of mTORC1 [70]. The European Prospective Investigation into Cancer and Nutrition confirmed that high intake of dairy protein is associated with an increased risk of PCa [71]. "
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    • "Further research should investigate the precise trafficking of milk exosomes, which most likely reach the systemic circulation of the milk recipient. Continued mTORC1-activation by milk-derived exosomal transfer of miR-21 may represent a persistently adverse health effect of regular milk and dairy product intake, which may play an important role for the development and progression of mTORC1-driven diseases of civilization [77-88]. In analogy to the postulated Trojan exosome hypothesis explaining the role of exosomes for the spread of RNA viruses [90], the milk exosome system too appears to function as a Trojan horse “transfecting” the neonate´s metabolism to ensure species-specific mTORC1-driven growth and anabolism. "
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