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Page 20 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

life. Remarkably, a 3.2-fold risk of advanced PCa was related to daily milk consumption in adolescence (vs.
less than daily), but not consumption in midlife or currently. Accordingly, frequent milk intake especially in
[168]
[10]
adolescence increases risk of advanced PCa . Lan et al. recently analyzed dietary data of the NIH-AARP
Diet and Health Study from 162,816 participants over a follow-up period of 14 years to investigate potential
associations for milk, cheese, ice cream, total dairy, and calcium intake at ages 12-13 years with incident
total (n = 17,729), advanced (n = 2348), and fatal PCa (n = 827). Their findings also support the contribution
of milk intake during adolescence for increased risk of PCa [Figure 3] .
[10]

Remarkably, milk consumption during adolescence has also been associated with acne vulgaris, the most
common inflammatory skin disease of adolescents in Western civilizations [601-607] . Notably, acne risk is
[608]
related with height at puberty . A cross-sectional population-based study on 6200 boys showed that 12-
15-year-old boys with acne were taller and heavier than those without acne . In analogy to PCa, both
[608]
androgens and IGF-1 induce the sebaceous gland disease acne vulgaris, which is associated with increased
glandular mTORC1 activity [609-611] . It is thus not surprising that an epidemiological association between
height and acne during adolescence and PCa during adult life has been observed [Figure 4] [612-614] .

DISPUTABLE STUDIES FOR MILK-PCA RISK EVALUATION
Cell cultures
There are several examples of investigations that apply questionable study designs to analyze the
[615]
relationship between milk consumption and PCa risk. Tate et al. added cow milk to LNCaP cells and
observed an increased growth rate of over 30%. However, under physiological conditions, a prostate cell will
never be exposed to whole milk. Transferable factors of milk, such as BCAAs, IGF-1, estrogens, aflatoxins,
exosomal MFG-E8, and exosomal miRs, may eventually reach the prostate and may accumulate during
persistent milk consumption.

[616]
Park et al. exposed PCa cells (LNCaP and PC3) and immortalized normal prostate cells (RWPE1) with
either 0.1 or 1 mg/mL of α-casein and total casein extracted from bovine milk. Whereas α-casein and total
casein did not affect the proliferations of RWPE1 cells, PC3 and LNCaP cells showed a significant but IGF-
1-independent increase in cell proliferation.

It is known that LNCaP and PC-3 cells take up leucine in a PI3K-AKT-dependent manner . Casein
[50]
hydrolysis may provide abundant leucine for PCa proliferation. Notably, total and α-casein contain high
amounts of leucine of 9.2 and 7.9 g/100g protein, respectively . Kim et al. studied gene expression
[617]
[618]
profiles of PC3 cells after exposure to α-casein and showed activated PI3K/AKT/mTORC1 signaling. Under
in vivo conditions, however, α-casein will never reach the prostate and PCa tissue, whereas α-casein-derived
BCAAs after intestinal hydrolysis and uptake into the blood circulation may affect PCa via BCAA-mTORC1
signaling.

Animal experiments
Bernichtein et al. performed an interventional animal study using two mouse models of fully penetrant
[619]
genetically induced prostate tumorigenesis that were investigated at the stages of benign hyperplasia
(probasin-Prl mice, Pb-Prl) or pre-cancerous prostatic intraepithelial neoplasia lesions (KIMAP mice). They
reported that mice were fed high milk diets (skim or whole milk) for 15-27 weeks depending on the kinetics
of prostate tumor development in each model. They reported that that high milk consumption did not
promote progression of existing prostate tumors when assessed at early stages of tumorigenesis.
Unfortunately, these investigators did not use regular commercial cow milk, but they instead exposed their
animals to milk protein powder re-suspended with water . It is thus conceivable that the impact of milk
[619]