title: Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence.
abstract: BACKGROUND
  Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms.
  
  
  METHODS
  A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies.
  
  
  RESULTS
  In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations.
  
  
  CONCLUSIONS
  There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. h.bronsveld@nki.nl.|Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands. h.bronsveld@nki.nl.
authors.forename: Heleen K
authors.initials: HK
authors.lastname: Bronsveld
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. basterbraak@gmail.com.
authors.forename: Bas
authors.initials: B
authors.lastname: ter Braak
authors.affiliation: Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway. Oystein.Karlstad@fhi.no.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Karlstad
authors.affiliation: Departments of Clinical Medicine and Endocrinology, Aalborg University, Aalborg, Denmark. p-vest@post4.tele.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Vestergaard
authors.affiliation: Departments of Clinical Medicine and Endocrinology, Aalborg University, Aalborg, Denmark. Jakob.Linde@auh.rm.dk.|Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital THG, Aarhus, Denmark. Jakob.Linde@auh.rm.dk.
authors.forename: Jakob
authors.initials: J
authors.lastname: Starup-Linde
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands. M.T.Bazelier@uu.nl.
authors.forename: Marloes T
authors.initials: MT
authors.lastname: Bazelier
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands. M.L.deBruin@uu.nl.
authors.forename: Marie L
authors.initials: ML
authors.lastname: De Bruin
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands. a.deboer@uu.nl.
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Medicines Evaluation Board (MEB), Utrecht, The Netherlands. cl.siezen@cbg-meb.nl.
authors.forename: Christine L E
authors.initials: CL
authors.lastname: Siezen
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. water_b@lacdr.leidenuniv.nl.
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.affiliation: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. jw.vd.laan@cbg-meb.nl.|Medicines Evaluation Board (MEB), Utrecht, The Netherlands. jw.vd.laan@cbg-meb.nl.|Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. jw.vd.laan@cbg-meb.nl.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van der Laan
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. mk.schmidt@nki.nl.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000209:etiology*; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000069036:Insulin Glargine / Q000009:adverse effects* / Q000627:therapeutic use*; D061986:MCF-7 Cells; D012306:Risk
chemical_list: D007004:Hypoglycemic Agents; D000069036:Insulin Glargine