3 years ago

COX2 induction: a mechanism of endocrine breast cancer resistance?

Brandi L. Clark, Landry K. Kamdem, Michael A. Murphy

Abstract

Purpose

Urine prostaglandin E2 (PGE2) levels have shown to be a risk factor of breast cancer, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to be beneficial in preventing breast cancer risk and/or recurrence with or without aromatase inhibitors. We hypothesized that the use of an aromatase inhibitor triggers the activation of the inflammatory pathway via release of PGE2.

Methods

A single oral 25 mg dose of an aromatase inhibitor (exemestane) was given to 14 healthy postmenopausal female volunteers. Blood and urine samples were collected between 0 and 72 h post-dosing for pharmacokinetic and pharmacodynamic analysis.

Results

Our findings showed that urine PGE2 levels were markedly increased 72 h after exemestane administration (average pre-dosing PGE2 levels, 4061.1 pg/mL vs. post-dosing average PGE2 levels, 10732.5 pg/mL, P = 0.001, Wilcoxon Rank Test). Out of 14 subjects enrolled in the study, one subject showed no change in PGE2; another showed a 23-fold decreased in PGE2; and the remaining 12 showed an average of 8.4-fold increase in PGE2 levels (range 1.3–30.5, standard deviation 9.2) after exemestane administration. We found no statistically significant correlations between fold increase in urine PGE2 levels and the pharmacokinetics of either exemestane or 17-hydroexemestane (major in vivo metabolite of exemestane).

Conclusion

Our results indicate that one of the pharmacological effects to aromatase inhibitors (e.g., exemestane) involves the activation of the inflammatory pathway via release of PGE2. Further in vitro mechanistic and in vivo translational studies designed to elucidate the role of this newly discovered effect are now warranted.

Publisher URL: https://link.springer.com/article/10.1007/s10549-017-4284-7

DOI: 10.1007/s10549-017-4284-7

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