title: Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk.
abstract: OBJECTIVE
  In experimental studies, enkephalins (ENKs) and related opioids have been implicated as negative regulators of breast cancer development by enhancing immune-mediated tumoral defense as well as directly inhibiting cancer cells. We hypothesized that plasma levels of ENKs are predictive of the long-term breast cancer risk. Therefore, our objective was to measure pro-ENK A, a surrogate for mature ENK, and evaluate its predictive value for the development of breast cancer in a large population of middle-aged women and an independent study population.
  
  
  METHODS
  We related pro-ENK in fasting plasma samples from 1,929 healthy women (mean age, 57.6 ± 5.9 years) of the Malmö Diet and Cancer study to breast cancer incidence (n = 123) during a median follow-up of 14.7 years. For replication, pro-ENK was related to risk of breast cancer (n = 130) in an older independent sample from the Malmö Preventive Project consisting of 1,569 women (mean age, 70.0 ± 4.4 years).
  
  
  RESULTS
  In the Malmö Diet and Cancer study, pro-ENK was inversely related to the risk of incident breast cancer, with a hazard ratio per each standard deviation increment of logarithm-transformed pro-ENK of 0.72 (95% CI, 0.62 to 0.85; P < .001). The linear elevation of risk over pro-ENK quartiles 3, 2, and 1, with the fourth quartile as a reference, was 1.38 (95% CI, 0.73 to 2.64), 2.29 (95% CI, 1.26 to 4.15), and 3.16 (95% CI, 1.78 to 5.60; for the trend, P < .001), respectively. These results were replicated in the Malmö Preventive Project, where the continuous odds ratio for incident breast cancer was 0.63 (95% CI, 0.52 to 0.76; P < .001) and the risk over pro-ENK quartiles 3, 2, and 1, where the fourth quartile was the reference, was 2.48 (95% CI, 1.25 to 4.94), 2.94 (95% CI, 1.50 to 5.77), and 4.81 (95% CI, 2.52 to 9.18; for the trend, P < .001), respecitvely.
  
  
  CONCLUSIONS
  Low fasting plasma concentration of the opioid precursor peptide pro-ENK is associated with an increased risk of future breast cancer in middle-aged and postmenopausal women.
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany. olle.melander@med.lu.se.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Manjer
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Svensson
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Hedblad
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Struck
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergmann
authors.affiliation: Olle Melander, Marju Orho-Melander, Jonas Manjer, Thomas Svensson, Peter Almgren, Peter M. Nilsson, Gunnar Engström, and Bo Hedblad, Lund University, Malmö; Signe Borgquist and Mattias Belting, Lund University, Lund; Olle Melander, Jonas Manjer, Peter M. Nilsson, Signe Borgquist, and Mattias Belting, Skåne University Hospital, Lund and Malmö, Sweden; Thomas Svensson, The University of Tokyo, Tokyo, Japan; Oliver Hartmann, Joachim Struck, and Andreas Bergmann, sphingotec, Hennigsdorf; and Andreas Bergmann, Waltraut Bergmann Foundation, Hohen Neuendorf, Germany.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000097:blood*; D015331:Cohort Studies; D004745:Enkephalins / Q000097:blood*; D005260:Female; D006801:Humans; D008875:Middle Aged; D010455:Peptides / Q000097:blood*; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood*; D012016:Reference Values; D012307:Risk Factors
chemical_list: D004745:Enkephalins; D010455:Peptides; D011498:Protein Precursors; C029992:proenkephalin