Stable Peptide of the Endogenous Opioid Enkephalin Precursor and Breast Cancer Risk

J Clin Oncol. 2015 Aug 20;33(24):2632-8. doi: 10.1200/JCO.2014.59.7682. Epub 2015 Jul 13.


Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Breast Neoplasms / blood*
  • Cohort Studies
  • Enkephalins / blood*
  • Female
  • Humans
  • Middle Aged
  • Peptides / blood*
  • Prospective Studies
  • Protein Precursors / blood*
  • Reference Values
  • Risk Factors


  • Enkephalins
  • Peptides
  • Protein Precursors
  • proenkephalin