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Page 12 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

the limit of detection. Several conjugated estrogen metabolites were identified: 17β-E2-3-glucuronide (71-
289 ng/L), E1-3-sulfate (60-240 ng/L), 17β-E2-3,17β-sulfate (< LOD to 30 ng/L), and E3-glucuronide (<
[376]
LOD of 25 ng/L) . Thus, endogenous and exogenous steroids derived from dairy products produced from
[377]
whole milk are a source of exogenous steroid exposure to humans .

Obesity has been proposed to be involved in the pathogenesis and more aggressive courses of PCa [378,379] .
Notably, a twofold elevation of serum E1 and 17β-E2 levels was observed in a group of morbidly obese
men . Thus, obese men with increased endogenous estrogen production may represent a vulnerable
[380]
group, especially during further exogenous estrogen exposure derived from milk and dairy products. There
is recent concern that estrogens represent an under-recognized contributor in PCa development and
progression [381,382] . Of notice, AR and ERα expression changes during PCa progression, both independently
[383]
and co-expressed . In high-grade prostatic intraepithelial neoplasia specimens (epithelium and stroma),
an increase in the population of double-positive (AR /ERα ) cells has been observed, whereas double-
+
+
-
-
negative (AR /ERα ) cells significantly decreased in advanced PCa, from 65% in benign prostate tissue to
30% in metastasis tissue .
[383]
There is extensive crosstalk among estrogens, androgens, and IGF-1 signaling in PCa cells. In LNCaP and
PC3 cells, E1 increased the level of AR and IGF-1 expression [384,385] . The upregulation of ERα and estrogen-
regulated progesterone receptor (PR) during PCa progression and hormone-refractory PCa suggests that
estrogens and progestins stimulate tumor growth . A potentially aggressive molecular subtype of PCa
[386]
exhibiting TMPRSS2-ERG gene fusion is regulated by ER. TMPRSS2-ERG expression increased by ERα
agonist but decreased by ERβ agonists . Thus, increasing evidence demonstrates that local estrogens
[386]
contribute to prostate carcinogenesis and tumor progression . It has also been reported in breast and
[387]
renal carcinoma cells that estrogens and IGF-1 have synergistic effects on tumor cell growth [388-391] . In fact,
IGF1R expression in PCa is upregulated by both androgens and estrogens sensitizing PCa cells to the
[392]
mitogenic effects of IGF-1 . Of note, mTORC1 has been identified as a critical checkpoint for estrogen
signaling . The downstream effector of mTORC1, the ribosomal S6K1, activates ERα via phosphorylation
[393]
of S167. ERα binding to Raptor promotes its translocation into the nucleus upon estrogen stimulation. In
addition, phosphorylation of ERα on S104/106 by mTOR kinase activates transcription of ER target
[394]
genes . The molecular crosstalk between mTORC1 and ERα in the pathogenesis of PCa may be
augmented by milk-mediated estrogens and milk-induced IGF-1, which synergistically activate mTORC1.
Treatment of LNCaP cells with androgen or E2 triggers simultaneous association of AR and ERβ with SRC
oncogene, activates the SRC/RAF-1/ERK-2 pathway, and stimulates cell proliferation . It has been
[394]
demonstrated in cortical neurons that ER protein interaction with p85, the regulatory unit of PI3K, leads to
[395]
activation of AKT and ERK1/2 . PCa stem cells lack AR explaining the resistance to androgen deprivation
therapy . However, PCa stem cells express classical (α and/or β) and novel (GPR30) ERs . Gene
[396]
[396]
expression profiles of CD133+ 4/CD44+ PCa stem cells showed that many ribosomal proteins and
translation initiation factors that constitute the mTOR complex were highly expressed .
[62]
Galactose
The lactose content of milk makes up around 2%-8% by weight. Lactose hydrolysis provides glucose and
galactose, which both activate mTORC1. The great majority of men in Western societies consuming milk
and dairy products is lactose-tolerant and can hydrolyze the disaccharide lactose into glucose and galactose.
The total galactose content of bovine milk is 2.4 g/100 g . Increased sugar consumption from sweetened
[397]
beverages was associated with increased risk of PCa for men in the highest quartile of sugar consumption
(HR = 1.21, 95%CI: 1.06-1.39), and there was a linear trend (P < 0.01) . In adults, hepatic galactose
[398]
elimination capacity is related to body weight and decreases slowly with age [399,400] . Notably, galactose