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Page 22 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

[UK Biobank cohort and Prostate Cancer Association Group to Investigate Cancer Associated Alterations
in the Genome (PRACTICAL) consortium]. Notably, per capita milk consumption in Finland (100.8 kg in
[621]
2020) is the highest in Europe . The approximations of milk intake were based on data of rs4988235
(LCT-12910C>T) of a sub-cohort of 12,722 participants of the European Prospective Investigation into
Cancer and Nutrition-InterAct study . The median milk consumption was 162 g/day (25th-75th
[622]
percentile, 37-300 g/day) and each additional milk intake increasing allele of rs4988235 was associated with
an increase in milk consumption of 17.1 g/day (P = 2 × 10 ). Unfortunately, rs4988235 was not available in
-7
the FinnGen consortium, and instead a proxy SNP (rs182549) in complete linkage disequilibrium was used.
A further limitation of Mendelian randomization studies is the fact that they do not present certain data on
the real daily amount of consumed milk, milk’s thermal processing method used in the analyzed study
cohorts, and the period of milk consumption during individual life periods as well as the potential impact of
maternal milk consumption on fetal prostate development, a critical period for nutritional epigenetic
programming of non-communicable diseases and non-hereditable genotypes [445,623-624] .

Meta-analyses and umbrella reviews
Epidemiological studies are also afflicted with severe insufficiencies, as no study reported in the literature
paid attention to the thermal processing of milk (pasteurization versus UHT), which significantly modifies
the survival and biological activity of milk EVs and MEX and their miRs [421,424,426] . Meta-analyses of meta-
analyses (so-called umbrella reviews ) mixing cohorts with low milk intake (Asian people) and cohorts
[625]
with high milk intake (US citizens and Europeans) further modified by different types of thermal milk
processing (predominant UHT processing in Southern European countries and preferential pasteurization
in Northern European countries) are very questionable scientific approaches from the point of milk’s
physiology. Furthermore, no study considered the complete spectrum of vulnerable periods of milk intake
during lifetime exposure on prostate tumorigenesis (fetal period, childhood, puberty with final prostate
gland differentiation, and adulthood) [Figure 3]. Nevertheless, it is astonishing that, despite these variances
and insufficiencies, the majority of dairy industry-independent meta-analyses and prospective studies were
able to relate milk consumption with an increased risk of PCa [10,12,13,14,168-175] , whereas a recent review series
sponsored by the Interprofessional Dairy Organization (INLAC) of Spain concluded that milk and dairy
[626]
product consumption is not associated with increased all-cause mortality and is not associated with an
[627]
increased risk of PCa .
CONCLUSION
As shown in this review, milk consumption provides a symphony of signals activating PI3K-AKT-mTORC1
and synergistically operates on overactivated PI3K-AKT-mTORC1 signaling pathways of PCa [21,154] . There is
no monocausal agent such as calcium, IGF-1, estrogens, BMMFs, or other single compounds that
exclusively promote cancer cell growth and PCa development. However, the molecular crosstalk of IGF-1,
androgens, estrogens, and milk-derived miRs functionally converge with well-characterized genetic and
epigenetic deviations of PI3K-AKT-mTORC1 signal transduction in PCa [22,23,63-68] .

Practices of veterinary medicine and dairy research to increase milk yield via holding dairy cows in
permanent pregnancy (increase in milk estrogens) [373-377] and selection for high-yield dairy cows (increase of
milk miR-148a) [469,470] combined with the induction of pasteurization and refrigeration technology changed
the magnitude and biological character of milk-derived signals compared to ancient times, when the total
amount and type of dairy intake were predominantly fermented milk products (cheese, yogurt, and
[426]
kefir) .