This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2009-0059OCv1 42/3/320    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ivanova, M. M. Articles by Klinge, C. M. Search for Related Content PubMed PubMed Citation Articles by Ivanova, M. M. Articles by Klinge, C. M.

Sex Differences in Estrogen Receptor Subcellular Location and Activity in Lung Adenocarcinoma Cells

¹ Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky

Correspondence and requests for reprints should be addressed to Carolyn M. Klinge, Ph.D., Department of Biochemistry & Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40292. E-mail: carolyn.klinge{at}louisville.edu

The role of estrogens in the increased risk of lung adenocarcinoma in women remains uncertain. We reported that lung adenocarcinoma cell lines from female, but not male, patients with non–small cell lung cancer respond proliferatively and transcriptionally to estradiol (E₂), despite equal protein expression of estrogen receptors (ER) and β. To test the hypothesis that nuclear localization of ER corresponds to genomic E₂ activity in lung adenocarcinoma cells from females, cell fractionation, immunoblot, and confocal immunohistochemical microscopy were performed. We report for the first time that E₂ increases phospho-serine-118-ER (P-ser118-ER) and cyclin D1 (CCND1) nuclear colocalization in H1793, but not A549 lung adenocarcinoma cells, derived from a female and male patient, respectively. ERβ was primarily in the cytoplasm and mitochondria, independent of E₂ treatment, and showed no difference between H1793 and A549 cells. E₂ induced higher transcription of endogenous ER-regulated CCND1 in H1793 than in A549 cells. Likewise, higher rapid, non-genomic E₂-induced extracellular signal–regulated kinase 1/2 activation was detected in H1793 compared with A549 cells, linking extracellular signal–regulated kinase activation to increased P-ser118-ER. Furthermore, E₂ increased cyclin D1 and P-ser118-ER nuclear localization in H1793, but not A549 cells. Together, our results indicate that nuclear localization of P-ser118-ER provides one explanation for sex-dependent differences in E₂-genomic responses in lung adenocarcinoma cell lines.

Key Words: estrogen receptor • cyclin D1 • phosphorylation • non–small cell lung cancer • sex differences

CLINICAL RELEVANCE Women have higher incidence of lung adenocarcinoma, a type of non–small cell lung cancer (NSCLC), compared to men. The mechanisms underlying the sex difference in NSCLC risk are multifactorial and complex. Here we show that nuclear localization of phospho-serine-118–estrogen receptor- provides one explanation for sex-dependent differences in estradiol-genomic responses in lung adenocarcinoma cell lines.

 

This article has been cited by other articles:

				G. Zhang, N. Yanamala, K. L. Lathrop, L. Zhang, J. Klein-Seetharaman, and H. Srinivas Ligand-Independent Antiapoptotic Function of Estrogen Receptor-{beta} in Lung Cancer Cells Mol. Endocrinol., September 1, 2010; 24(9): 1737 - 1747. [Abstract] [Full Text] [PDF]