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homeostasis of prostate epithelial cells.

Calcium-independent milk-induced mTORC1 activation
[125]
Current research interest focuses on the pathogenic role of milk-induced elevations of IGF-1 in PCa . In
fact, overwhelming evidence accumulated over two decades supports the view that increased circulating
levels of IGF-1 as well as local IGF-1/IGF1 receptor (IGF1R) signaling promote PCa initiation and
progression [126-151] . The perception of milk has changed from a “pure food source” to an “endocrine and
epigenetically active biologic system”, promoting IGF-1-PI3K-AKT-mTORC1 signaling substantially
augmented by milk’s exosomal miRs [20,152,153] . Milk signaling functionally synergizes with dominant
oncogenic driver mutations of PCa including androgen signaling, disturbed DNA repair, and mutations
enhancing PI3K/AKT/mTORC1 signaling [21,154] .

Despite recent progress in milk’s molecular biology and its sophisticated physiological functions [20,152,153] ,
nutrition science and dairy industry-supported reviews present a positive view on milk as a nutrient for
metabolic health, providing valuable proteins, macronutrients, oligosaccharides, calcium, vitamins, and
other micronutrients [155-159] . None of those studies in the field of nutrition and epidemiological research
appreciates milk’s biological role as an mTORC1-driving system of mammalian evolution physiologically
restricted to the postnatal growth period [20,152,153,160] . In fact, there is growing evidence in various disciplines of
medicine that milk consumption is associated with adverse health effects, increasing overall mortality [161-165] .
Milk consumption has been related to several common mTORC1-driven cancers of Western civilization,
especially PCa [166-175] , breast cancer [176-183] , hepatocellular carcinoma [184-187] , and diffuse large B-cell
lymphoma . Notably, overactivated mTORC1 signaling is a common hallmark of PCa [21,22,27,57-61] , breast
[188]
cancer [189-194] , hepatocellular carcinoma [195-200] , and diffuse large B-cell lymphoma [201-204] . Based on a recent
[154]
review of the literature, Vasconcelos et al. confirmed a possible relationship between milk consumption
and mTORC1-mediated initiation and progression of PCa.

Oncogenic activation of the PI3K/AKT/mTORC1 pathway is a frequent aberration in PCa
pathogenesis [22,23] . There is an intimate crosstalk between the PI3K/AKT/mTORC1 cascade and multiple
other signaling pathways that promote PCa progression [22,23] . Specifically, PI3K/AKT/mTORC1 signaling
cooperates with AR, MAPK, and WNT signaling cascades [22,23] . To elucidate milk’s impact on mTORC1-
[20]
dependent translation and PCa initiation and progression , deeper insights into milk’s signaling
[21]
pathways are mandatory.
mTORC1 is the cell’s central hub for the regulation of nutrient- and growth factor-dependent cell growth
and anabolism [205-211] . To fulfill its biological function as promotor of postnatal growth, milk activates five
major pathways stimulating mTORC1 via: (1) growth factors including growth hormone (GH), insulin, and
IGF-1; (2) amino acids, especially BCAAs; (3) milk fat-derived palmitic acid; (4) the milk sugar lactose β-D-
galactopyranosyl-(1→4)-D-glucose; and (5) epigenetic modifiers, especially milk exosome (MEX)-derived
miRs. Activated PI3K-AKT-mTORC1 signaling in PCa is presented in Figure 2A. Figure 2B illustrates
superimposed milk and milk miR signaling over-activating the PI3K-AKT-mTORC1 signaling cascade in
PCa cells.

Milk-derived essential amino acids (prototype leucine) activate mTORC1, increasing cell proliferation.
MEX-derived miRs augment mTORC1 signaling and modify transcriptional activity in PCa. miR-148a and
miR-21 suppress PTEN, which is commonly mutated or deleted in PCa. Increased AKT activity results in
nuclear translocation of FoxO1, a key nuclear suppressor of AR, RUNX2, and sterol regulatory element
binding protein 1. Milk-derived estrogens (E) may induce further transcription of IGF-1. RUNX2 is