title: Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations.
abstract: OBJECTIVE
  Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis.
  
  
  METHODS
  Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib.
  
  
  RESULTS
  Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib.
  
  
  CONCLUSIONS
  Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients.
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University; tatsuro@surg2.med.kyushu-u.ac.jp.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.affiliation: Clinical Research Institute, National Kyushu Cancer Center;
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Shimokawa
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kitahara
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shimamatsu
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University; Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd., Gotemba; and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Tsukihisa
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka;
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takenoyama
authors.affiliation: Clinical Research Institute, National Hospital Organization Beppu Medical Center, Beppu, Japan.
authors.forename: Tokujiro
authors.initials: T
authors.lastname: Yano
authors.affiliation: Authors' Affiliations: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University;
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D012333:RNA, Messenger; D001141:Aromatase; D066246:ErbB Receptors