Akt-Mediated Phosphorylation and Activation of Estrogen Receptor α Is Required for Endometrial Neoplastic Transformation in Pten+/− Mice

Abstract

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 a variety of mechanisms, including regulation of cell death and cell proliferation. However, it is still unclear which of the many downstream pathways are critical in each different tissue, in vivo. Loss of PTEN is the earliest detectable genetic lesion in the estrogen-related type I (endometrioid) endometrial cancer. Pten +/À mice develop endometrial neoplastic lesions with full penetrance, thus providing a model system to dissect the genetic and biochemical events leading to the transition from normal to hyperplastic and neoplastic endometrial epithelium. Here, we show that loss of Pten in the mouse endometrium activates Akt and results in increased phosphorylation of estrogen receptor A (ERA) on Ser 167 . ERA phosphorylation results, in turn, in the activation of this nuclear receptor both in vivo and in vitro, even in the absence of ligand, and in its increased ability to activate the transcription of several of its target genes. Strikingly, reduction of endometrial ERA levels and activity dramatically reduces the neoplastic effect of Pten loss in the endometrium, in contrast to complete estrogen depletion. Thus, we provide for the first time in vivo evidence supporting the hypothesis that loss of Pten and subsequent Akt activation result in the activation of ERA-dependent pathways that play a pivotal role in the neoplastic process. (Cancer Res 2006; 66(7): 3375-80)

Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells

“…Moreover, unopposed oestrogen signalling, a well-recognized risk factor for EEC (Amant et al, 2005;Shang, 2006), has been shown to enhance PI3K/Akt activity through binding of oestrogen receptor a (ERa) to the p85a regulatory subunit of PI3K . Conversely, recent studies in heterozygote Pten þ /À mice, which develop EECs with full penetrance, demonstrated that enhanced PI3K/Akt signalling leads to targeted phosphorylation of ERa on Ser167 and ligand-independent activation, thus mimicking a hyperestrogenic environment (Vilgelm et al, 2006). Furthermore, FOXO1 engages in the transcriptional cross-talk with ERa through physical interaction (Schuur et al, 2001), suggesting an important role for FOXO1 in mediating oestrogen responses in target tissues.…”

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

“…18 Loss of PTEN in mouse endometrium has lead to increased phosphorylation of estrogen receptor-a, which resulted in activation of this nuclear receptor even in the absence of ligand, leading to enhanced ability to activate the transcription of its target genes, and therefore contribute to the neoplastic transformation of the endometrial cells. 53 Even though PTEN mutations are frequently present in tumors with MSI, little is known about the interrelation between MSI and estrogen exposure. MSI positive colon cancers have been associated with very low levels of estrogen receptors, 54 while studies in breast carcinoma have yielded controversial results.…”

Expression, activation, and role of AKT isoforms in the uterus

“…Evidences have shown that E 2 induced the phosphorylation of AKT (S473) through PI3K as well as estrogen receptor alpha (ERa; Guo et al 2006). Furthermore, loss of PTEN has been shown to activate AKT, which in turn is responsible for the phosphorylation of ERa on S167; this phosphorylation subsequently activates it (Vilgelm et al 2006). As stated previously, chemoresistance is a major challenge in the treatment of EC.…”