Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis

Abstract

Purpose: To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3).

Methods: Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise.

Results: One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression.

Conclusion: IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk.

Keywords: Insulin-like growth factors; Mechanistic pathway; Meta-analysis; Milk; Prostate cancer; Systematic review.

Fig. 1

Flow diagram depicting the inclusion and exclusion process during the meta-analysis and the number of papers categorized into each study type for milk–IGF and IGF–PCa

Fig. 2

Infographic to illustrate overall associations between milk intake and PCa risk (including advanced risk for IGF-I and IGFBP-3). Notes: numbers next to the circles indicate the total number of participants across all studies, the size of each circle is proportionate to the p value (larger circles indicate lower p values), the “+” and “−” symbols indicate the direction of effect, the two semi-transparent circles in IGF-I and IGFBP-3 PCa Risk indicate advanced PCa risk (with associated p values the lower of the two p values), and p values are all calculated using Stouffer’s Z score method of combining p values. *Milk is used as a collective term for milk, dairy products and dairy proteins

Fig. 3

Albatross plots for each outcome: a IGF-I and b IGFBP-3, stratified by exposure. Each point represents a single study included in the meta-analysis, with the effect estimate (represented as a p value), plotted against the number of subjects included within each study. Effect estimates are standardized beta coefficients. Where p values were presented as <0.05, they were plotted as 0.05 as a conservative estimate

Fig. 4

Forest plot for all studies that presented data on circulatory levels of IGF-I in relation to PCa risk, stratified by study design (prospective vs retrospective) and PSA-detected PCa cases

Fig. 5

Forest plot for all studies that presented data on circulatory levels of IGFBP-3 in relation to PCa risk, stratified by study design (prospective vs retrospective) and PSA-detected PCa cases