title: Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
authors.forename: Sean
authors.identifier: http://orcid.org/0000-0002-7966-0700
authors.initials: S
authors.lastname: Harrison
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Lennon
authors.affiliation: IGFs & Metabolic Endocrinology Group, School of Clinical Sciences at North Bristol, Southmead Hospital, BS10 5NB, Bristol, UK.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holly
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
authors.forename: Julian P T
authors.initials: JPT
authors.lastname: Higgins
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Gardner
authors.affiliation: IGFs & Metabolic Endocrinology Group, School of Clinical Sciences at North Bristol, Southmead Hospital, BS10 5NB, Bristol, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Perks
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tan
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|Cardiff University, Cardiff, UK.
authors.forename: Cath
authors.initials: C
authors.lastname: Borwick
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Pauline
authors.initials: P
authors.lastname: Emmet
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: Jeffreys
authors.affiliation: CLAHRC West, University of Bristol, Bristol, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Northstone
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Sabina
authors.initials: S
authors.lastname: Rinaldi
authors.affiliation: School of Oral and Dental Sciences,, University of Bristol, Bristol, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Pease
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Vicky
authors.initials: V
authors.lastname: Vilenchick
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.|National Institute for Health Research Biomedical Research Unit in Nutrition, Diet and Lifestyle, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, BS2 8AE, Bristol, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK. s.j.lewis@bristol.ac.uk.|MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK. s.j.lewis@bristol.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lewis
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D008892:Milk / Q000009:adverse effects*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012306:Risk
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
keywords: Insulin-like growth factors; Mechanistic pathway; Meta-analysis; Milk; Prostate cancer; Systematic review