Serum estrogen receptor beta mediated bioactivity correlates with poor outcome in lung cancer patients

Objectives: The role of estrogen signaling in lung cancer remains unresolved. We investigate the influence of serum estrogenic compounds and estrogen receptor (ER alpha and ER beta) mediated bioactivity on lung cancer outcomes. Materials and methods: Serum samples were collected from 222 postmenopausal Chinese patients diagnosed with lung cancer in five Singapore hospitals. Levels of the estrogenic compounds estradiol and estrone were measured using liquid chromatography tandem mass spectrometry. Free estradiol levels were calculated based on sex hormone binding globulin levels. ER alpha- and ER beta-mediated bioactivity in serum samples were analyzed using reporter gene bioassays in human cells. Results and conclusion: High ER beta-mediated bioactivity predicted poorer lung cancer survival (p = 0.001) on multivariable Cox regression analysis with adjustment for age, stage of tumor, smoking status, body mass index and histology. In comparison, levels of estrogens and ER alpha-mediated bioactivity were not associated with prognosis. Compared to the lowest tertile of ER beta-mediated bioactivity, patients in the middle and highest tertiles had HR (95%CI) 1.60 (1.10-2.33) and 1.93 (1.32-2.82) (p for trend = 0.001) higher risk of death from lung cancer. Using Kaplan-Meier survival curves, patients with high ER beta-mediated bioactivity correlated with poorer overall survival (p = 0.033). ER beta-mediated bioactivity did not differ in terms of age, use of hormone replacement therapy, smoking, stage of tumor or histological subtype. High ER beta-mediated bioactivity levels in patients' serum were associated with poorer prognosis in lung cancer patients. Our findings suggest that that compound(s) other than endogenous estrogens may be exerting this ER beta bioactivity and studies to identify these compounds or groups of compounds need to be performed. Furthermore, the measurement of ER beta activity in sera could potentially serve as a prognostic marker to predict lung cancer survival, and selective blockage of ER beta signaling may have a role in lung cancer therapy. (C) 2014 Elsevier Ireland Ltd. All rights reserved.