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Page 2 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the
initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most
common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

Keywords: Aflatoxins, branched-chain amino acids, estrogens, exosomes, growth hormone, IGF-1, microRNAs,
milk, mTORC1, prostate cancer

INTRODUCTION
Prostate cancer (PCa) is the sixth leading cause of cancer death among men worldwide and is expected to
[1]
reach 2.3 million new cases and 740,000 deaths by 2040 . The highest incidence rates are observed in
Australia, New Zealand, North America, Western and Northern Europe, and the Caribbean. The lowest
[2,3]
rates are found in South-Central Asia, Northern Africa, and Southeast and Eastern Asia . According to the
Global Cancer Statistics 2020 (GLOBOCAN), PCa contributes to 7.3% of all cancers . The median age of
[3]
[4]
PCa diagnosis is 68 years, while 10% of new cases in the USA are diagnosed in men aged ≤ 55 years .
Western diet and lifestyle have been linked to PCa prevalence [5-10] . Substantial lifestyle changes took place in
Japan after World War 2, where a 20-fold increase in milk intake was associated with a 25-fold increased
death rate of PCa .
[11]
Accumulated evidence confirms that cow milk consumption is positively related to the risk of PCa [12-14] . Milk
and dairy products are substantial components of nutrition in Western industrialized countries as
compared to Asian or North African countries [Figure 1] . In 2019, the per capita cow milk consumption
[15]
in Germany was 49.5 L . Higher milk consumption is reported in Scandinavian countries. In Sweden, the
[16]
[17]
annual per capita milk consumption declined from 2007 to 2018 from 130.5 to 98.2 L . The annual per
capita milk consumption in the USA declined from 89.4 kg in 2000 to 64.0 kg in 2019 . In Asian
[18]
populations, milk consumption is much lower. In 2019, Chinese people consumed on average only 12.5 kg
of milk and dairy products per year .
[19]
It is the intention of this review to relate milk-derived signaling pathways with the molecular pathology of
PCa. To understand milk’s impact on the pathogenesis of PCa, it is of key importance to appreciate milk’s
biological nature as an endocrine and epigenetic system generated by the lactation genome to promote
mechanistic target of rapamycin complex 1 (mTORC1)-driven postnatal growth, translation, and
[20]
anabolism , a critical mode of cell signaling maintained by the consumption of commercial dairy milk .
[21]
Evidence is presented that the nutrigenomic signaling of milk converges with common oncogenic
aberrations of PCa cells.

GENETIC DEVIATIONS ACTIVATING PI3K-AKT-MTORC1 IN PCa

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K)-AKT (protein kinase B)-mammalian
target of rapamycin complex 1 (mTORC1) pathway is a frequent finding in PCa that promotes
tumorigenesis, tumor progression, and resistance to therapy [22,23] . PI3K-AKT-mTORC1 signaling is elevated
in a high proportion of PCa and castration-resistant PCa (CRPC) [24-27] . Reduced expression of phosphatase
and tensin homolog deleted on chromosome 10 (PTEN), a critical tumor suppressor of PCa, correlates with
PCa progression and poor prognosis . In fact, PTEN is one of the most frequently deleted genes in
[28]
PCa [29-34] . Notably, PTEN loss in primary PCa specimens correlates with high Gleason score and advanced
disease . Aberrant gene expression of PI3K pathway components is common in PCa and occurs in 42%
[35]
and 100% of primary and metastatic PCa specimens, respectively [36-40] . It is of crucial importance that the
PI3K-AKT-mTORC1 cascade interacts with androgen receptor (AR), RAS/mitogen-activated protein kinase