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Page 18 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

RUNX2 Increased RUNX2 expression; bone metastasis, increases PSA [53,55,56,352] Increased 31% in blood mononuclear cells 6 h after milk consumption [359]
transcription; is suppressed by nuclear FoxO1
DNMT1 Reduced expression associated with EMT and cancer stem cell [105] Bovine MEX miR-148a suppresses DNMT1 expression [418,438,443]
phenotype
Calcium Thought to be involved in PCa pathogenesis (early studies) [115-119,124] Major mineral of milk; questionable influence of dairy calcium on the prostate as [116]
circulatory calcium levels are maintained within close limits

derived IGF-1, constituting a major part of circulating IGF-1, is an important endocrine factor involved in a variety of physiological and pathological
processes . Notably, locally derived IGF-1 cannot replace liver-derived IGF-1 for the regulation of a large number of other parameters including GH
[567]
[567]
secretion, cortical bone mass, and prostate size .
IGF-1 is a regulator of intrauterine growth, and circulating concentrations are reduced in intrauterine growth-restricted fetuses . During fetal life, IGF-1 is
[568]
mostly secreted by the placenta . Positive correlations among birthweight (BW), gestational age, and umbilical cord serum IGF-1 levels have been
[569]
reported [569,570] . Thus, increased BW may represent systemic fetal exposure to IGF-1, which may affect prostate branching morphogenesis that may be over-
stimulated by maternal milk intake raising maternal systemic IGF-1 levels [231-236] .

[571]
Downstream PI3K-AKT-mTORC1 signaling plays a crucial role for prostatic morphogenesis . PI3K/mTORC1 signaling is necessary for prostatic epithelial
bud invasion of surrounding mesenchyme. The balance of PI3K and downstream mTORC1/C2 activity as a critical regulator of prostatic epithelial
[571]
morphogenesis .
RUNX2 plays an important role in branching morphogenesis of the prostate . IGF-1-PI3K-AKT-mediated nuclear extrusion of FoxO1 enhances nuclear
[572]
RUNX2 activity . miR-21, which is transferred via MEX, accumulates in the placenta and fetal tissues [420,437] and may further augment RUNX2-dependent
[53]
prostate morphogenesis and stem cell activation . RUNX2 was detected during early prostate development (E16.5). In adult mice, RUNX2 was expressed in
[572]
basal and luminal cells of ventral and anterior lobes. Prostate-selective deletion of RUNX2 severely inhibited growth and maturation of tubules in the anterior
prostate and reduced expression of stem cell markers and prostate-associated genes . Milk-induced changes of growth trajectories during pregnancy and
[572]
fetal development via IGF-1 and miR-21 signaling may thus disturb early prostate morphogenesis, increasing subsequent PCa risk in adult life. Increased cow
milk intake during the first trimester of pregnancy has recently been positively associated with general and abdominal visceral fat mass and lean mass at the
age of 10 years .
[573]

BW and PCa risk
BW, an indicator of fetal growth, is related to placental weight and has been identified as a risk factor of PCa [575-578] . Compared with twins with a BW of
[574]
2500-2999 g, the hazard ratio (95%CI) for twins with a higher BW (≥ 3000 g) corresponded to 1.22 (0.94-1.57). In analyses within twin pairs, in which both