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Figure 1. (A) Per capita consumption (kg) of milk and milk-derived products worldwide in 2017. (B) Comparison of per capita
consumption (kg) of milk and milk-derived products during 1961-2017 in Western Europe, the United States, and China according to
Our World in Data [15] .

[22]
(MAPK), and Wingless (WNT) signaling pathways . Of note, AKT-mediated phosphorylation and nuclear
extrusion of FoxO1, a nuclear suppressor of AR [41-45] , activates androgen signaling [43,44] . Notably, AR regulates
L-type amino acid transporters (LATs) that are of pivotal importance for the cellular uptake of mTORC1-
activating branched-chain amino acids (BCAAs), especially leucine . In comparison to other protein
[46]
sources, whey proteins exhibit the highest amounts of leucine [47,48] . LAT1 and LAT3 mediate the uptake of
leucine and other essential amino acids. PCa cells express LAT1 and LAT3 to maintain sufficient levels of
leucine required for mTORC1-dependent cancer cell growth [46,49] . LAT inhibition decreased PCa cell growth
and mTORC1 activity. AR-mediated LAT3 expression maintained levels of amino acid influx through ATF4
regulation of LAT1 expression after amino acid deprivation . High levels of LAT3 are observed in primary
[46]
[46]
disease, whereas increased levels of LAT1 are detected in PCa metastasis after hormone ablation .
Epidermal growth factor (EGF)-activated PI3K/AKT signaling also stimulates cellular leucine import
through LAT3 in PCa cell lines . LAT inhibition could thus be an effective therapeutic strategy against
[50]
PCa [51,52] .

Furthermore, overactivation of PI3K-AKT signaling attenuates the inhibitory effect of FoxO1 on RUNT-
related transcription factor 2 (RUNX2) transcriptional activity, promoting PCa cell migration and
invasion . Increased RUNX2 activation has been related to metastatic disease , especially tumor
[54]
[53]
progression in the bone [55,56] .
The frequency of common genetic deviations of genes in the PI3K-AKT-mTORC1 pathway in PCa is
[39]
[22]
presented in Table 1 according to the works of Shorning et al. and Armenia et al. .
Overactivated mTORC1 signaling plays a crucial role in PCa initiation and progression [57-62] .
Zabala-Letona et al. identified alterations in tumor tissue production of decarboxylated S-
[59]
adenosylmethionine and polyamine synthesis resulting from mTORC1-dependent regulation of S-
adenosylmethionine decarboxylase 1 (AMD1) stability. AMD1 is upregulated in human PCa with activated
[62]
[59]
mTORC1 . Activated mTORC1 has also been reported in CD133+ 4/CD44+ PCa stem cells .
Taken together, substantial evidence underlines the importance of genetic deviations in PCa cells and PCa
cancer stem cells enhancing PI3K-AKT-mTORC1 signaling.