Wnt-7a is upregulated by norethisterone in human endometrial epithelial cells: a possible mechanism by which progestogens reduce the risk of estrogen-induced endometrial neoplasia M.K. Oehler a,b,c , I.Z. MacKenzie a , D. Wallwiener c , R. Bicknell b , M.C.P. Rees a, * a Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK b Molecular Angiogenesis Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK c Department of Obstetrics and Gynaecology, University of Tuebingen, Tuebingen, Germany Received 9 February 2002; received in revised form 28 April 2002; accepted 30 April 2002 Abstract Progestogens are added to oestrogen in hormone replacement therapy regimens to reduce the risk of endometrial cancer. We have performed in vitro studies analysing gene expression of isolated normal endometrial epithelia cells (NEE) treated with estradiol and the progestogen norethisterone acetate (NETA). We report here for the first time upregulation of the Wnt-7a gene by NETA in estrogen treated NEE. Wnt genes are a large family of developmental genes associated with cellular responses such as oncogenesis. We therefore suggest that upregulation of Wnt-7a may be associated with the antineoplastic effects of progestogens on the endometrium. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hormone replacement therapy; Endometrial cancer; Progestogens; Norethisterone acetate; Gene expression array; Wnt-7a 1. Introduction Estrogen replacement therapy (ERT) alleviates menopausal symptoms and conserves bone mass. However, unopposed ERT is associated with an increased incidence of endometrial hyperplasia and progression to endometrial carcinoma in postmeno- pausal women who retain their uteri [1]. The addition of progestogen either sequentially or continuously was found to reduce the risk of endometrial hyperpla- sia and carcinoma and has become the standard course of therapy [2]. Despite the clear evidence that progestogens reduce the risk of endometrial neoplasia, little is known about their mechanism of action. Various antiestrogenic mechanisms have been described including down- regulation of estrogen receptor expression, enhance- ment of estrogen metabolism by estradiol-17b dehy- drogenase and decrease of DNA synthesis [3]. We have performed in vitro-studies analysing gene expression of isolated normal endometrial epithelial cells (NEE) treated with estradiol (E 2 ) and the synthetic progestogen norethisterone acetate (NETA) using Cancer Letters 186 (2002) 75–81 0304-3835/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3835(02)00259-8 www.elsevier.com/locate/canlet * Corresponding author. Tel.: 144-1865-220-024; fax: 144- 1865-220-310. E-mail address: margaret.rees@obstetrics-gynaecology. oxford.ac.uk (M.C.P. Rees). Abbreviations: ECGS, endothelial cell growth supplement; ER, estrogen receptor alpha; ERT, Estrogen replacement therapy; DES, diethylstilbestrol; NEE, normal endometrial epithelial cells; NES, normal endometrial stromal cells; E 2 , estradiol; NETA, norethisterone acetate; RT, reverse transcription; PCR, polymerase chain reaction