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Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37 Page 11

with a γ-secretase inhibitor reduced the formation of CD44-ICD. Overexpression of RUNX2 augmented the
expression of metastasis-related genes (e.g., MMP-9 and osteopontin), which resulted in increased
[353]
migration and tumorsphere formation . There is compelling evidence that RUNX2 enhances cell growth
[354]
and responses to androgen and TGFβ in PCa cells . Remarkably, RUNX2 stimulates AR responsive
expression of the PSA . Both RUNX1 and RUNX2 cooperate with prostate-derived ETS factor to activate
[354]
[355]
the transcription of PSA upstream regulatory region . Recently, a cooperation between AR and RUNX2 in
the stimulation of oncogenes such as invasion-promoting SNAIL family transcription factor SNAI2 has
been demonstrated . RUNX2 not only is a master organizer of gene transcription in developing and
[356]
maturing osteoblasts , which is related to the physiological function of milk increasing linear and skeletal
[357]
growth [261,262] , but it also promotes PCa bone metastasis [54,55,358] . It is thus of critical concern that cow milk-
derived phytanic acid may induce γ-secretase-mediated CD44-ICD-RUNX2 nuclear signaling . Of
[56]
importance, Baier et al. demonstrated that the expression of RUNX2 increased by 31% in blood
[359]
mononuclear cells 6 h after commercial cow milk consumption in adult healthy volunteers compared to
baseline.

[360]
Plasma phytanic acid concentrations have been significantly associated with intake of dairy fat . Higher
phytanic acid intake, although unrelated to the risk of localized PCa, was associated with increased risks of
[342]
advanced PCa predominantly by phytanic acid obtained from dairy products , whereas no overall
association has been detected between serum phytanic and pristanic acid levels and PCa risk [342,361] . In
contrast, Xu et al. reported that serum levels of phytanic acid among PCa patients were significantly
[362]
higher than those of unaffected controls, suggestive of an association between phytanic acid and PCa risk
[Figure 2].

Increasing evidence links PCa risk with polymorphisms in the α-methylacyl-CoA racemase (AMACR) gene
and branched-chain fatty acids derived from specific sources of dietary fats [363-366] . AMACR is a catalyst in
peroxisomal β-oxidation of branched-chain fatty acids found in milk and dairy products . AMACR
[367]
expression is actually downregulated in hormone-refractory metastatic tissue relative to the primary
tumor . An association between low AMACR expression at diagnosis and an increased risk of
[368]
biochemical recurrence and fatal PCa has been reported . Furthermore, lower AMACR intensity was
[369]
associated with higher PSA levels and more advanced clinical stage at diagnosis, and there was a non-
[370]
significant trend for higher risk of lethal outcomes . In contrast, other studies report AMACR
overexpression as an early event in prostate tumorigenesis that may precede morphologic evidence of
malignant transformation [371,372] .

Estrogens
Dairy cows continuously lactate throughout almost their entire pregnancy, explaining increased amounts of
estrogens and progesterone in commercial milk . A significant increase in serum estrone (E1) and
[373]
2
progesterone levels has been shown in men and children who consumed 600 mL/m of cow milk. In
addition, urine levels of E1, estradiol (E2), estriol (E3), and pregnanediol significantly increased in all
consumers, allowing the conclusion that milk-derived estrogens were absorbed . Milk of Swiss Holstein
[373]
cows exhibited average hormone levels of E1 = 159 ng/kg, 17β-E2 = 6 ng/kg, 17α-E2 = 31 ng/kg, 4-
androstenedione = 684 ng/kg, progesterone = 15,486 ng/kg, 17-hydroxyprogesterone = 214 ng/kg, cortisol =
[374]
235 ng/kg, and cortisone = 112 ng/kg, whereas E3 was below the limit of detection . According to
Malekinejad et al. , the major cow milk estrogens were free and deconjugated E1 (6.2-1266 ng/L), α-E2
[375]
(7.2-322 ng/L), and β-E2 (5.6-51 ng/L), whereas E3 was below the detection limit. The calculated daily
[376]
[375]
estrogen intake through milk consumption was 372 ng . In commercial milk samples, Tso et al.
confirmed that E1 (23-67 ng/L) was the major free estrogen, whereas E2 and E3 concentrations were below