This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jones, M. B. Articles by Maihle, N. J. Search for Related Content PubMed PubMed Citation Social Bookmarking                   What's this?

The Granulin-Epithelin Precursor Is a Steroid-Regulated Growth Factor in Endometrical Cancer

Mayo Clinic, Rochester, Minnesota; Duke University, Durham, North Carolina; Walter Reed Army Hospital, Washington, DC; Yale University, New Haven, Connecticut; Mayo Clinic, Gynecologic Surgery, 200 First St. SW, Rochester, MN 55905; jones.monica{at}mayo.edu

Aletta P. Houwink, MD,

Brandi K. Freeman, BS

Tammy M. Greenwood, MS

Jacqueline M. Lafky, MS

Wilma L. Lingle, PhD

Andrew Berchuck, MD

G. Lawrence Maxwell, MD

Karl C. Podratz, MD, PhD

Nita J. Maihle, PhD

Mayo Clinic, Rochester, Minnesota; Duke University, Durham, North Carolina; Walter Reed Army Hospital, Washington, DC; Yale University, New Haven, Connecticut

Objectives: The majority of endometrical cancers arise as a result of estrogen stimulation, the molecular targets of which remain incompletely defined. We hypothesize that the granulin-epithelin precursor (GEP) may be one such target. In this study, we examined the frequency of GEP and estrogen receptor (ER) co-expression in human endometrial cancers. Once we established the co-expression of GEP with the estrogen receptor we examined the potential estrogen regulation of GEP expression, as well as the functional significance of GEP expression in vitro.

Methods: Double immunofluorescence and confocal microscopy were used to compare GEP and ER expression among 41 endometrial cancers. The effects of estradiol and tamoxifen treatment on GEP expression in two endometrial cancer cell lines, KLE and HEC-1-A, were assessed through reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The antiproliferative effect of GEP silencing by short hairpin (sh)RNA, was evaluated in HEC-1-A cells using an MTT assay.

Results: GEP co-expression with ER was observed in 63% of the cancers examined. A two- to fivefold increase in GEP expression with estradiol and/or tamoxifen treatment was observed in KLE cells. Silencing of GEP in HEC-1-A cells using shRNA resulted in a decrease in proliferation among transfected cells.

Conclusions: Co-expression of GEP and ER in endometrial cancer cells, and the regulation of GEP by estrogen, suggests a role for GEP in steroid-mediated endometrial cancer cell growth. Further characterization of GEP as a steroid-mediated growth factor in these cells may broaden our understanding of endometrial cancer biology and also provide guidance in the development of novel therapeutic targets.

Key Words: Endometrial cancer • estrogen receptor • growth factors • granulin-epithelin precursor • PC-derived growth factor • steroid hormones • hormone-regulated cancers

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