title: Serum estrogen receptor beta mediated bioactivity correlates with poor outcome in lung cancer patients.
abstract: OBJECTIVE
  The role of estrogen signaling in lung cancer remains unresolved. We investigate the influence of serum estrogenic compounds and estrogen receptor (ERα and ERβ) mediated bioactivity on lung cancer outcomes.
  
  
  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. ERα- and ERβ-mediated bioactivity in serum samples were analyzed using reporter gene bioassays in human cells.
  
  
  CONCLUSIONS
  High ERβ-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 ERα-mediated bioactivity were not associated with prognosis. Compared to the lowest tertile of ERβ-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 ERβ-mediated bioactivity correlated with poorer overall survival (p=0.033). ERβ-mediated bioactivity did not differ in terms of age, use of hormone replacement therapy, smoking, stage of tumor or histological subtype. High ERβ-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 ERβ bioactivity and studies to identify these compounds or groups of compounds need to be performed. Furthermore, the measurement of ERβ activity in sera could potentially serve as a prognostic marker to predict lung cancer survival, and selective blockage of ERβ signaling may have a role in lung cancer therapy.
authors.affiliation: Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore.
authors.forename: Vanessa W
authors.initials: VW
authors.lastname: Lim
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597 Singapore.
authors.forename: Wei-Yen
authors.initials: WY
authors.lastname: Lim
authors.affiliation: Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore.
authors.forename: Yinhan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597 Singapore.
authors.forename: Adeline
authors.initials: A
authors.lastname: Seow
authors.affiliation: Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228 Singapore. Electronic address: obgyel@nus.edu.sg.
authors.forename: Eu Leong
authors.initials: EL
authors.lastname: Yong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D047628:Estrogen Receptor alpha / Q000097:blood; D047629:Estrogen Receptor beta / Q000097:blood*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta
keywords: ERβ-mediated estrogenic activity; Estrogen receptors; Estrogens; Lung cancer; Postmenopausal women; Survival