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


METHODS
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) alpha (A549 + ERalpha) or ERbeta (A549 + ERbeta) 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 ERalpha- or ERbeta-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ERalpha or A549 + ERbeta, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + ERalpha and A549 + ERbeta 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 ERalpha- or ERbeta-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.
Niikawa
Hiromichi
H
Department of Pathology, Tohoku University School of Medicine, Japan.
Suzuki
Takashi
T
Miki
Yasuhiro
Y
Suzuki
Satoshi
S
Nagasaki
Shuji
S
Akahira
Junichi
J
Honma
Seijiro
S
Evans
Dean B
DB
Hayashi
Shin-Ichi
S
Kondo
Takashi
T
Sasano
Hironobu
H
D001141:Aromatase / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002853:Chromatography, Liquid; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000032:analysis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008175:Lung Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators; D021241:Spectrometry, Mass, Electrospray Ionization
D020847:Estrogen Receptor Modulators; D004967:Estrogens; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D001141:Aromatase