Journal of the Society for Gynecologic Investigation

 

Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

http://mc.manuscriptcentral.com/rsci

Click here for free access to the SAGE eReference platform!

Sign In to gain access to subscriptions and/or personal tools.
This Article
Right arrow Full Text (PDF)
Right arrow References
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gielen, S. C.J.P.
Right arrow Articles by Blok, L. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gielen, S. C.J.P.
Right arrow Articles by Burger, C. W.
Right arrow Articles by Kühne, L. C.M.
Right arrow Articles by Hanifi-Moghaddam, P.
Right arrow Articles by Blok, L. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?
Journal of the Society for Gynecologic Investigation, Vol. 12, No. 7, e55-e66 (2005)
DOI: 10.1016/j.jsgi.2005.08.003

Analysis off Estrogen Agonism and Antagonism of Tamoxifen, Raloxifene, and ICI182780 in Endometrial Cancer Cells: A Putative Role for the Epidermal Growth Factor Receptor Ligand Amphiregulin

Susanne C.J.P. Gielen, MD

Curt W. Burger, MD, PhD

Liesbeth C.M. Kühne, BsC

Payman Hanifi-Moghaddam, PhD

Department of Obstetrics and Gynecoogy and Department of Reproduction and Development, Erasmus MC, Rotterdam, The Netherlands

Leen J. Blok, PhD

Department of Obstetrics and Gynecoogy and Department of Reproduction and Development, Erasmus MC, Rotterdam, The Netherlands l.blok{at}erasmusmc.nl

Objectives: In different tissues, estrogens, selective estrogen receptor modulators (SERMs), and anti-estrogens exert different biologic activities. For the endometrium, estradiol and tamoxifen induce proliferation, and because of this, tamoxifen treatment of breast cancer patients results in a two- to sevenfold increased risk for development of endometrial cancer. Use of raloxifene, or the anti-estrogen ICI182780, does not result in such an increased risk. The objective of the current study was to generate and analyze gene expression profiles that reflect the transcriptional response of the human endometrium to estradiol, SERMs like tamoxifen and raloxifene, and anti-estrogens like ICI182780.

Methods: Transient transfections were performed to analyze the transcriptional response of ECC-1 cells to estradiol, tamoxifen, raloxifene, and ICI182780. Subsequently, to reveal the molecular mechanism of action, gene expression profiles were generated and some of the observed regulated genes were confirmed by Northern blotting. Biostatistical methods were employed to analyze the expression profile results further, and amphiregulin effects on ECC-1 cell signaling were investigated using Northern and Western blotting, and 3H-thymidine incorporation.

Results: Analysis of the profiles revealed that estradiol, tamoxifen, raloxifene, and ICI182780 influence the same biologic processes, but they do so via regulation of different sets off genes. Upon construction of a genetic network it was observed that the largest possible network centered on epidermal growth factor (EGF) receptor signaling. Furthermore, the EGF receptor ligand amphiregulin was differentially regulated by all four ligands. Next it was shown that amphiregulin indeed could stimulate EGF receptor signaling in ECC-1 cells. Based on these results, it was hypothesized that EGF receptor signaling could differentially be affected by estrogen, tamoxifen, raloxifene, and ICI182780 because these four compounds differentially regulate the EGF receptor ligand amphiregulin.

Conclusions: Regulation of amphiregulin coincides with the described in vivo effect of the four ligands on the endometrium. Therefore, it is possible that modulation of EGF receptor signaling is a significant player in estrogen-agonistic growth of the endometrium and needs to be investigated further.

Key Words: Estrogens • SERMs • anti-estrogens • endometrium • amphiregulin • EGF receptor


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?