The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Abstract

This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse 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.

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

“…Importantly, DLBCL cells take up exosomes and their RNAs [ 274 ]. This observation highlights the importance of EVs and exosomes promoting aberrant biological programming of recipient cells, including pre-metastatic niche formation and tumor progression [ 274 , 275 ], also demonstrated in other malignancies such as B-cell chronic lymphocytic leukemia [ 276 ], melanoma [ 277 , 278 ], pancreatic cancer [ 279 ], hepatocellular carcinoma [ 280 , 281 ], breast cancer [ 282 , 283 ], and prostate cancer [ 284 , 285 ]. Of note, CLL-derived microvesicles (MV) can activate the AKT/mTORC1/p70S6K/hypoxia-inducible factor-1α axis in CLL-bone marrow stromal cells (BMSCs) with the production of vascular endothelial growth factor, a survival factor for CLL B-cells.…”

Milk exosomal microRNAs: friend or foe?—a narrative review

“…The use of concentrated MEX either native or uploaded with drugs will expose the recipient to increased amounts of intrinsic MEX miRs that may exert desired gene-regulatory effects in the target tissue but may adversely affect other non-target tissues. Bovine MEX showed beneficial effects in inflammatory bowel diseases and states of fibrosis (47)(48)(49)(50)(51)469), but may promote hyperphagia, obesity, T2DM, cancer and neurodegeneration (88,90,221,277,296,351) (Table 7). Certainly, human MEX are supportive for the newborn infant and contribute to the superiority of breastfeeding compared to formula.…”

“…Common cancers of industrialized societies such as breast cancer (BCa) and prostate cancer (PCa), which show a risk association with milk consumption (279)(280)(281)(282), exhibit exosomal overexpression of miR-21 in the circulation and tumor tissues (283)(284)(285)(286)(287)(288)(289)(290). Thus, persistent bovine MEX miR-21 exposure may enhance mTORC1 signaling promoting tumor initiation and progression (291)(292)(293)(294)(295)(296). Furthermore, MEX miR-mediated destabilization of p53 (86,88,174,176) may promote cancer development and disturb tumor immunity (297)(298)(299).…”

DodecaRNAs (doRNAs) are abundant in cow’s milk and differentially enriched in milk ultracentrifugation fractions

“…Overexpression of the doRNA-binding protein hnRNP A2/B1 in prostate cancer (54), its importance in the progression of this malignancy and for the resistance to apoptosis (55) would make of this protein a "hub"and association with doRNAs (19)-potentially linking doRNAs and prostate cancer. While the link between milk consumption and prostate cancers remains controversial, with inconsistent evidence in the general population of men (56)(57)(58), milk and its bioactive components, including exRNAs, might affect the etiology of prostate cancer, more likely in those with digestive tracts more permeable to mEVs, as seen for bacterial lipopolysaccharide (LPS)bearing EVs (59,60). This link, although speculative, calls for further investigations.…”