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Keywords:

  • breast cancer;
  • cysteinyl leukotriene receptors;
  • tamoxifen;
  • prognosis;
  • tumor cell migration

Abstract

The fact that breast cancer patients with local or distal dissemination exhibit decreased survival, promotes a search for novel mechanisms to suppress such tumor progression. Here, we have determined the expression of proinflammatory cysteinyl leukotriene receptors (CysLTRs) in breast tumor tissue and their signaling effect on breast cancer cell functions related to tumor progression. Patients with breast tumors characterized by high CysLT1R and low CysLT2R expression levels exhibited increased risk of cancer-induced death in univariate analysis for both the total patient group (hazard ratio [HR] = 2.88, 95% confidence interval [CI] = 1.11–7.41), as well as patients with large (>20 mm) tumors (HR = 5.08, 95% CI = 1.39–18.5). Multivariate analysis revealed that patients with large tumors exhibiting high CysLT1R and low CysLT2R expression levels had a significantly reduced survival, also when adjusted for established prognostic parameters (HR = 7.51, 95% CI = 1.83–30.8). In patients with large (>20 mm) tumors, elevated CysLT2R expression predicted an improved 5-year survival (log-rank test p = 0.04). Surprisingly, for longer time periods, this prognostic value was lost. This disappearance coincided with the termination of hormonal treatment. Tamoxifen preserved and even induced transcription of CysLT2R, but not CysLT1R, in estrogene receptor-positive MCF-7 breast cancer cells. This elevated CysLT2R expression decreased, even below the level of untreated cells, when tamoxifen was withdrawn. CysLT2R signaling reduced MCF-7 cell migration, but had no effect on either proliferation or apoptosis. Our data indicate that low CysLT1R together with high CysLT2R expression levels might be useful parameters in prognostication and treatment stratification of breast cancer patients.