Intratumoral Estrogens and Estrogen Receptors in Human Non–Small Cell Lung Carcinoma

^{1 1}Department of Pathology, Tohoku University School of Medicine; ²Departments of Pathology and ³Molecular Medical Technology, Tohoku University School of Health Sciences; ⁴Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; ⁵Department of Thoracic Surgery, Ishinomaki Red Cross Hospital, Ishinomaki, Japan; ⁶Teizo Medical Co. Ltd., Kawasaki, Japan; and ⁷Novartis Institutes for BioMedical Research Basel, Oncology Research, Basel, Switzerland

^* To whom correspondence should be addressed. E-mail: t-suzuki{at}patholo2.med.tohoku.ac.jp.

	Abstract

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) (A549 + ER) or ER (A549 + ER) 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 ER- or ER-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ER or A549 + ER, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + ER and A549 + ER 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 ER- or ER-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.

Key Words: Lung cancer (00-00-20), Hormone receptors and diagnosis/prognosis (04-06-02), Hormone synthesis, metabolism and inhibitors (04-06-03)