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Page 16 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

Bovine milk and meat factors
Small circular single-stranded DNA (ssDNA) sequences have been detected in commercial milk [529-533] . These
replication-competent bovine meat and milk factors (BMMF1 and BMMF2) are a specific class of infectious
agents spanning between bacterial plasmid and circular ssDNA viruses with similarities to the genomic
[534]
structure of hepatitis deltavirus . BMMF Rep protein has been found in close vicinity of CD68+
[535]
macrophages in the interstitial lamina propria adjacent to colorectal cancer tissues . BMMF1 DNA was
isolated from the same tissue regions. Compared to cancer-free controls, Rep and CD68+ exhibited
[535]
increased expression in peritumor cancer tissues . At present, no experimental data on BMMFs in PCa
tissue are available .
[536]
Aflatoxins
Ruminants metabolize aflatoxin B1 (AFB1) ingested by contaminated food to aflatoxin M1 (AFM1). AFM1
is the hydroxylated mycotoxin that is excreted into milk [537-540] . The increase of AFM1 concentrations in milk
of maize-fed cows due to the climate change is a matter of concern . The International Agency for
[541]
Research on Cancer classified AFB1 and AFM1 as human carcinogens of group 1 [542,543] . AFM1 is relatively
stable during pasteurization, storage, and processing [544-546] . Scaglioni et al. analyzed AFB1 and AFM1
[547]
concentrations of pasteurized and UHT milk and found levels for both aflatoxins in the range of 0.7-
1.5 μg/L. Raw and concentrated milk samples exhibited maximum average AFM1 concentrations of
1.7 μg/L, exceeding the concentration levels permitted by legislation .
[547]
[548]
Smith et al. demonstrated a rapid uptake of AFB1 by the rat and dog prostate. Notably, the expression of
androgen-inducible aldehyde reductase, a member of the aldo-keto reductase superfamily, exhibits 80%
amino acid sequence homology with rat aflatoxin B1 aldehyde reductase and is associated with growth-
related processes in regrowing rat prostate after androgen replacement . Aflatoxin B1 aldehyde
[549]
reductases, specifically the NADPH-dependent aldo-keto reductases of rat (AKR7A1) and human
(AKR7A2), are known to metabolize the AFB1 dihydrodiol by forming AFB1 dialcohol [550,551] . Milk-derived
aflatoxins may thus modify aldo-keto reductase activities, which are in the focus of recent PCa
research [552-554] . Furthermore, it has been demonstrated in lung cancer cell lines that AFB1 upregulates
insulin receptor substrate 2; induces SRC, AKT, and ERK1/2 phosphorylation; and stimulates cancer cell
migration, which was inhibited by saracatinib , a kinase inhibitor under investigation in the treatment of
[555]
PCa [556-559] . Thus, milk-derived aflatoxins may amplify SRC- and AKT-mediated prostate carcinogenesis.
Table 3 summarizes all milk-derived signals that increase PI3K-AKT-mTORC1 signaling.

MILK’S IMPACT ON DEVELOPMENTAL PERIODS OF PCA
Fetal prostate growth
Prostate organogenesis includes organ specification, epithelial budding, branching morphogenesis,
[560]
canalization, and cytodifferentiation . Activated AR‐positive murine epithelium initiates budding at
E17.5. Ductal expansion and branching continues during postnatal development, leading to formation of a
fully functional prostate by puberty [561-563] .

IGF-1 plays a key role in fetal prostate development . Prostate glands from 44-day-old IGF-1-deficient
[561]
mice were smaller than those from wild-type mice and exhibited fewer terminal duct tips and branch points
and deficits in tertiary and quaternary branching, indicating a specific impairment in gland structure .
[564]
Furthermore, IGF-1 controls prostate fibromuscular development of the prostatic gland, whereas IGF-1
inhibition prevented both fibromuscular and glandular development in eugonadal mice . Castration
[565]
rapidly decreased local IGF-1 levels and inhibited its effects in the ventral prostate in mice, whereas local
injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice but had no effect
in castrated animals . Studies using mice with liver-specific IGF-1 knockout have demonstrated that liver-
[566]