Characterization of an estrogen-regulated growth factor in endometrial cancer

MB Jones, MDa, A Houwinka, WL Lingle, PhDa, EC Kohn, MDb, A Berchuck, MDc, KC Podratz, MD, PhDa, NJ Maihle, PhDa

a Mayo Clinic, Rochester, MN United States, b National Cancer Institute, Bethesda, MD United States, c Duke University Medical Center, Durham, NC United States

Aims: Non-selective estrogen (E2) antagonists, such as tamoxifen, have opposing effects on breast and endometrial cells by complex molecular mechanisms. Identifying E2 regulated growth factors may broaden our understanding of these mechanisms and predict a high risk group for endometrial cancer and progression. The granulin-epithelin precursor (GEP), a 68 – 88kDa glycoprotein, was recently shown to be up-regulated by E2 treatment of estrogen receptor (ER) positive breast cancer cells. We hypothesize GEP, may participate in endometrial cancer cell growth and may be a predictor of poor outcome for select patients. Our objectives are to investigate GEP production, secretion and potential E2 regulation in vitro and in vivo. Methods: GEP localization was determined by immunocytochemical staining in two endometrial cancer cell lines, KLE and RL95-2. Levels of GEP and ER production were determined by Western blot analysis of lysates from these cell lines as well as from Ishikawa cells. Results: Diffuse cytoplasmic staining of GEP was observed in both cell lines. All three cell lines expressed the 88kDa form of GEP. Normalization of expression to beta actin revealed the highest levels of GEP and ER in Ishikawa cell lines. Conclusions: Preliminary experiments suggest that GEP expression may be correlated with ER expression levels. These results provide us with a useful model system for further characterization of GEP regulation by E2 in endometrial cancer. Defining new growth factors for hormone mediated endometrial cancer may provide new prognosticators and therapeutic targets for a subset of patients at risk for poor outcome.

KEY WORDS: granulin-epithelin precursor, tamoxifen, reproductive tract.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.