TI - Discussion . AB - Estrogen receptor is a member of the nuclear receptor superfamily and function as ligand -dependent transcription factor in the nucleus to mediate estrogen signaling . However , accumulating evidence demonstrate that there is a rapid ( within seconds or minutes ) estrogen signaling which cannot be explained by genomic signaling pathway that usually takes hours to function [25,26] . Recently , we found that ER-alpha36 was expressed in ER-positive and ER-negative breast cancer cells [27] , suggesting that ER-alpha36 expression is regulated differently from ER-alpha66 . In the present study , we found that ER-alpha36 is expressed mainly on the plasma membrane in ER-alpha66-negative endometrial cancer Hec1A cells and ER-alpha36 mediates membrane-initiated MAPK/ERK and PI3K/Akt pathways induced by testosterone . It has been reported that endometrial cancer risk is increased in both pre - and postmenopausal women with elevated plasma levels of testosterone [5,28] . Early in the neoplastic process , abnormal endometrial cells can locally produce estrogens from the plasma pool of androgen , and thus gain a growth advantage independent of circulating estrogens [29,30] . The local concentration of estrogens in endometrial cancer was reported to be higher than that in the blood and the endometrium of cancer-free women [31] . Indeed , previous studies have shown that aromatase activity is increased in endometrial cancer cells , but not normal endometrial cells [32] . Moreover , elevated circulating androgen has also been associated with hyperplasia of the endometrium , which generally precedes and accompanies the occurrence of type I endometrial carcinomas [33] . Aromatase is a key enzyme in the synthesis of estrogen that is responsible for binding of testosterone and catalyzes the series of reactions eventually resulting in estrogen production [34] . Previous reports demonstrated that aromatase is present in endometrial cancer tissue , suggesting that aromatase plays a role in converting testosterone into mitogenic estrogens in endometrial tissue [24,35] . Recently , a significant correlation has been found between aromatase immunoreactivity and poor prognosis in patients with endometrial carcinoma [36] . This positive linkage indicates that local aromatase contributes to tumor progression through the in situ formation of estrogens . Here , we show that testosterone stimulates the activation of both ERK1/2 and the Akt signaling pathways in endometrial cancer Hec1A cells that lack expression of ER-alpha66 and AR . Therefore , it is possible that the estrogen produced localy from testosterone in endometrial cells could bind ER-alpha36 and then activate MAPK/ERK and PI3K/Akt pathways . PCOS is one of the most common endocrinopathies in humans , which affects about 10% of women of reproductive age [37] . PCOS is characterized by the production of endogenous progesterone and absence of ovulations and an increased secretion of ovarian androgen [38] . The association between PCOS and endometrial carcinoma has been reported for many years . The risk of development from PCOS to endometrial cancer was examined in 1270 women with chronic anovulation . This study identified the excess risk of endometrial cancer to be 3.1 [95% CI , 11-73] [33,39] . PCOS is a key risk factor especially for endometrial cancer among young , premenopausal women [40] . It is possible that increased rate by which androgen is converted to estrogen via aromatization , which then stimulates both the MAPK/ERK and the PI3K/Akt signaling pathways through ER-alpha36 . The activation of ERK and Akt is involved the development of endometrial cancer [15,41] . Epidemiological , experimental and clinical result have shown that estrogen plays a key role in the development and progression of endometrial cancer [1] . Aromatase inhibitor inhibits local estrogen production in postmenopausal women and is used to treat postmenopausal women with breast cancer [42] . The large trials demonstrated that aromatase inhibitor contributed to improved disease-free survival and good tolerability in breast cancer patients [43] . Recently , aromatase inhibitor has been shown to reduce proliferation and increase apoptosis in endometrial cancer in vitro [44,45] . Letrozole is a competitive nonsteroidal aromatase inhibitor that suppresses over 85% of circulating levels of estrogen and over 98% of aromatization in postmenopausal patients with breast cancer [46] . In our study , we found that letrozole abrogated testosterone-induced ERK and Akt PHOSphorylation , suggesting that aromatase might be involved in testosterone carcinogenesis .