27 - 30 May 2005

DANGEROUS LIAISONS: PTEN/AKT/ER-alpa CROSSTALK IN THE DEVELOPMENT OF ENDOMETRIAL CANCER Antonio Di Cristofano PhD Fox Chase Cancer Center Philadelphia, PA USA

PTEN is a tumor-suppressor gene frequently mutated in human cancers. In vitro and in vivo studies have shown that PTEN can exert its tumor suppressive function through different mechanisms, including regulation of cell death and cell proliferation. However, it is still unclear which specific pathways are critical in vivo in different tissues. Loss of PTEN is the earliest detectable genetic lesion in type I (endometrioid) endometrial cancer. Pten+/- mice develop with full penetrance endometrial neoplastic lesions, thus providing a model system to dissect the genetic and biochemical events leading to the transition from normal to hyperplastic and neoplastic endometrial epithelium.

We have shown that loss of Pten in the mouse endometrium correlates in vivo with elevated Akt activity that results in increased phosphorylation of oestrogen receptor alpha (ER-alpha) on serine 167. ER-alpha phosphorylation results, in turn, in the hormone-independent activation of this nuclear receptor both in vivo and in vitro, and in the ability to activate the transcription of a number of its target genes. Strikingly, reduction of endometrial ER-alpha levels consequent to neonatal diethylstilbestrol (DES) administration completely reverses the neoplastic effect of Pten loss in the endometrium.

Thus, we have provided for the first time in vivo evidence supporting the hypothesis that loss of Pten and subsequent Akt activation result in the activation of ER-alpha-dependent pathways that play a pivotal role in the neoplastic process and may thus be amenable to chemopreventive and therapeutic intervention.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract