474 Current Drug Targets, 2010, 11, 474-481 1389-4501/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. The Epithelial-Mesenchymal Transition and the Estrogen-Signaling in Ovarian Cancer D. Gallo * , C. Ferlini and G. Scambia Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy Abstract: Epithelial ovarian cancer is the leading cause of death for gynecological cancer in most of the Western world; lethality ensues from the occurrence of occult metastasis within the peritoneal cavity, a process requiring the acquisition of capacity for migration and invasiveness by ovarian tumor cells (metastatic phenotype), and characterized by a complex series of interrelated cellular events. Unlike most carcinomas that dedifferentiate during neoplastic progression with loss of epithelial E-cadherin (epithelial to mesenchymal transition, EMT), ovarian carcinomas undergo transition to a more epithelial phenotype, early in tumor progression, with increased E-cadherin expression. Subsequent reacquisition of mesenchymal features is observed in late-stage tumors, and loss of E-cadherin expression or function is a factor in ovarian cancer progression. Changes in E-cadherin expression are indicative of the phenotypic plasticity that occurs in ovarian cancer, with a variety of signal transduction pathways impinging on the regulation of E-cadherin levels or subcellular distribution. Among them, the Snail transcription family, consisting of members SNAIL and SLUG, is thought to be mainly involved in the repression of E-cadherin expression, leading to EMT. E-cadherin, SNAIL, and SLUG also represent crucial targets of estrogen signaling. In this review, we discuss recent advances in the understanding of the role of estrogen signaling in the complex network underlying the phenotypic plasticity in ovarian cancer. Insight into the mechanisms involved will allow rational drug designs, aimed at the molecules critical to cellular signaling. Keywords: Ovarian cancer, estrogens, EMT, E-cadherin, SNAIL, SLUG. INTRODUCTION Ovarian cancer is the sixth most common cancer and the fifth leading cause of cancer death among women in the USA [1]; in European women, in 2006, it accounted for about 3.9% of all female cancers [2]. The epithelial tumors represent 80% to 90% of ovarian malignancies in the United States and Western Europe [3], and usually dominate the data from cancer registries. Initial therapy for epithelial ova- rian cancer consists of surgery; debulking surgery is per- formed for advanced stage of the disease in order to decrease tumor burden, and it is followed by chemotherapy, the current standard of care being platinum plus taxane. Ovarian cancer is recognized to be one of the most chemotherapy- sensitive malignancies, with 70–80% of newly diagnosed pa- tients exhibiting a response to primary platinum plus taxane chemotherapy; despite this fact, the majority of women who present with advanced ovarian cancer will experience recurrence. The probability of response to second-line che- motherapy depends mostly on the relapse-free interval. Patients with ovarian cancer that is refractory to a platinum- based chemotherapy, or that relapse within 6 months after its discontinuation are considered to be platinum resistant [4]. Unfortunately, regimens used as second-line therapy in such situations have a low response rate, and are associated with severe side effects that negatively influence the quality of life, and necessitate long stays in hospital and intensive palliative care [4]. Patients ultimately die of complications associated with progressive disease. The importance of estrogen signaling in the development and progression of ovarian cancer has been assumed to be *Address correspondence to this author at the Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Largo A. Gemelli, 8 – 00168, Rome, Italy; Tel: +39 06 3013337; Fax: +39 06 3051160; E-mail: d.gallo@rm.unicatt.it less significant than for breast or endometrial cancers, although clinical data, animal experiments, and receptor studies have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endo- crine related, and hormone-dependent. Preclinical studies have indicated a cancer promoting effects of estrogens on ovarian cancer growth, mostly by up-regulation of proteins involved in cell growth and metastasis [5, 6]. In postmeno- pausal patients with epithelial ovarian cancer, plasma con- centrations of estradiol, progesterone, androstenedione and testosterone were directly correlated with tumor volume and FIGO stage, and changes in hormonal concentrations (with the exception of testosterone) reflected the response of ovarian cancer to therapy [7]. Consistently, the use of exogenous hormones for menopause-related symptoms has been associated with an increased risk of ovarian cancer incidence or mortality, with recent studies showing that prolonged periods of hormone replacement therapy (HRT) use ( 5–10 years) confer an approximately 1.5–2.0- fold increase in risk [8]. In contrast, decreased risk of ovarian cancer follows the use of oral contraceptives (OC), with 5 years of oral OC use conferring a 30–50% reduction in cancer risk [8]. The protective effect of oral contraceptives could be interpreted as supportive of the estrogen hypothesis, as oral contraceptive use decreases ovarian estrogen produc- tion, and early to midfollicular phase circulating estrogens are maintained during use. Other Authors, however, suggest that chronic suppression of ovulation reduces cancer risk by decreasing recurrent ovarian injury [9]. The significance of anti-estrogenic intervention in the treatment of ovarian carcinoma has been emphasized by the fact that these drugs will inhibit the growth of ovarian carcinoma in vitro and in vivo [10, 11]. Clinical trials with the aromatase inhibitor letrozole, which acts by depleting levels of estrogen available to the Estrogen Receptors (ERs),