Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma

Hiromichi Niikawa, Takashi Suzuki, Yasuhiro Miki, Satoshi Suzuki, Shuji Nagasaki, Junichi Akahira, Seijiro Honma, Dean B. Evans, Shinichi Hayashi, Takashi Kondo, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

173 Citations (Scopus)


Purpose: The possible involvement of gender-dependent factors has been suggested in human non-small cell lung carcinomas (NSCLC), but their precise roles remain largely unclear. Therefore, we examined intratumoral estradiol concentrations in NSCLC to examine local actions of estrogens in NSCLC. Experimental Design: Fifty-nine frozen specimens of NSCLC were available for liquid chromatography/electrospray tandem mass spectrometry to study intratumoral estradiol concentrations. In addition, A549 NSCLC cells stably expressing estrogen receptor (ER) α (A549 + ERα) or ERβ (A549 + ERβ) were used in vitro studies. Results: Forty-three (73%) of 59 NSCLC showed higher concentration of estradiol in carcinoma tissues than the corresponding nonneoplastic lung tissues from the same patient, and intratumoral estradiol concentrations were significantly (P = 0.0002 and 2.2-fold) higher than the corresponding nonneoplastic lungs. The intratumoral concentration of estradiol was positively correlated with aromatase expression, tumor size, and Ki-67 status in ERα- or ERβ-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ERα or A549 + ERβ, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + ERα and A549 + ERβ cells expressed aromatase. The cell proliferation level in these cells was significantly increased under treatment with testosterone, and it was inhibited by addition of the aromatase inhibitor letrozole. Conclusions: These results suggest that estradiol is locally produced in NSCLC mainly by aromatase and plays an important role in the growth of ERα- or ERβ-positive NSCLC. Therefore, use of selective ER modulators and/or aromatase inhibitors may be clinically effective in NSCLC that are positive for both ER and aromatase.

Original languageEnglish
Pages (from-to)4417-4426
Number of pages10
JournalClinical Cancer Research
Issue number14
Publication statusPublished - 2008 Jul 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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